Spg stimulation

ABSTRACT

A method for treating a subject is provided, including applying electrical stimulation to a site of the subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve. The stimulation is configured to excite nervous tissue of the site at a strength sufficient to induce at least one neuroprotective occurrence selected from the group consisting of: an increase in cerebral blood flow (CBF) of the subject, and a release of one or more neuroprotective substances, and insufficient to induce a significant increase in permeability of a blood-brain barrier (BBB) of the subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of:

(a) U.S. patent application Ser. No. 12/983,409, filed Jan. 3, 2011, which is a continuation of U.S. patent application Ser. No. 12/052,788, filed Mar. 21, 2008, now abandoned, which is a divisional of U.S. patent application Ser. No. 11/349,020, filed Feb. 7, 2006, now U.S. Pat. No. 7,561,919, which is a continuation-in-part of U.S. patent application Ser. No. 10/783,113, filed Feb. 20, 2004, now U.S. Pat. No. 7,117,033; and

-   -   (b) U.S. patent application Ser. No. 13/849,673, filed Mar. 25,         2013, which is a divisional of U.S. patent application Ser. No.         13/223,929, filed Sep. 1, 2011, now U.S. Pat. No. 8,406,869,         which is a divisional of U.S. patent application Ser. No.         11/465,381, filed Aug. 17, 2006, now U.S. Pat. No. 8,055,347,         which claims the benefit of U.S. Provisional Patent Application         60/709,734, filed Aug. 19, 2005.

All of the above-mentioned patent applications are assigned to the assignee of the present application and are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to medical procedures and devices, e.g., electrical devices. More specifically, the invention relates to the use of electrical devices for implantation in the head, for example, in the nasal cavity, and/or to the use of stimulation for treating medical conditions.

BACKGROUND OF THE INVENTION

The blood-brain barrier (BBB) is a unique feature of the central nervous system (CNS) which isolates the brain from the systemic blood circulation. To maintain the homeostasis of the CNS, the BBB prevents access to the brain of many substances circulating in the blood.

The BBB is formed by a complex cellular system of endothelial cells, astroglia, pericytes, perivascular macrophages, and a basal lamina. Compared to other tissues, brain endothelia have the most intimate cell-to-cell connections: endothelial cells adhere strongly to each other, forming structures specific to the CNS called “tight junctions” or zonula occludens. They involve two opposing plasma membranes which form a membrane fusion with cytoplasmic densities on either side. These tight junctions prevent cell migration or cell movement between endothelial cells. A continuous uniform basement membrane surrounds the brain capillaries. This basal lamina encloses contractile cells called pericytes, which form an intermittent layer and probably play some role in phagocytosis activity and defense if the BBB is breached. Astrocytic end feet, which cover the brain capillaries, build a continuous sleeve and maintain the integrity of the BBB by the synthesis and secretion of soluble growth factors (e.g., gamma-glutamyl transpeptidase) essential for the endothelial cells to develop their BBB characteristics.

PCT Publication WO 01/85094 and U.S. Pat. Nos. 7,120,489 and 7,190,998 to Shalev and Gross, which are assigned to the assignee of the present patent application and are incorporated herein by reference, describe apparatus for modifying a property of a brain of a patient, including electrodes applied to a sphenopalatine ganglion (SPG) or a neural tract originating in or leading to the SPG. A control unit drives the electrodes to apply a current capable of inducing (a) an increase in permeability of a blood-brain barrier (BBB) of the patient, (b) a change in cerebral blood flow of the patient, and/or (c) an inhibition of parasympathetic activity of the SPG.

U.S. Pat. No. 6,853,858 to Shalev, which is assigned to the assignee of the present application and is incorporated herein by reference, describes apparatus for delivering a Non Steroidal Anti-Inflammatory Drug (NSAID) supplied to a body of a subject for delivery to at least a portion of a central nervous system (CNS) of the subject via a systemic blood circulation of the subject. The apparatus includes a stimulator adapted to stimulate at least one site of the subject, so as to cause an increase in passage of the NSAID from the systemic blood circulation across a blood brain barrier (BBB) of the subject to the portion of the CNS, during at least a portion of the time that the NSAID is present in the blood, the site selected from the list consisting of: a sphenopalatine ganglion (SPG), an anterior ethmoidal nerve, a posterior ethmoidal nerve, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG, a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, a nasopalatine nerve, a posterior nasal nerve, an infraorbital nerve, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve.

US Patent Application Publication 2004/0220644 to Shalev et al, which is assigned to the assignee of the present application and is incorporated herein by reference, describes a method for treating a subject, comprising positioning at least one electrode at at least one site of the subject for less than about 3 hours, applying an electrical current to the site of the subject, and configuring the current to increase cerebral blood flow (CBF) of the subject, so as to treat a condition of the subject. The site is selected from the list consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve. Also described is an apparatus comprising an elongated support element having a length of between about 1.8 cm and about 4 cm, and having a proximal end and a distal end; one or more electrodes fixed to the support element in a vicinity of the distal end thereof; a receiver, fixed to the support element in a vicinity of the proximal end thereof; and a control unit, adapted to be coupled to the receiver, and adapted to drive the electrodes to apply an electrical current to tissue of the subject, and configure the current to have a pulse frequency of between about 10 Hz and about 50 Hz, an amplitude of between about 0.2 V and about 10 V, a pulse width of between about 50 microseconds and about 5 milliseconds, and, in alternation, on periods of between about 1 second and about 2 minutes, and off periods of between about 1 second and about 2 minutes.

The following patent application publications, all of which are assigned to the assignee of the present application and are incorporated herein by reference, may be of interest: WO 03/090599, WO 03/105658, WO 04/044947, WO 04/043217, WO 04/043334, and WO 05/030118.

US Patent Application Publication 2003/0176898 to Gross et al., which is assigned to the assignee of the present application and is incorporated herein by reference, describes apparatus for treating a condition of an eye of a subject, comprising a stimulator adapted to stimulate at least one site of the subject, such as the SPG, so as to treat the eye condition.

US Patent Application Publication 2005/0159790 to Shalev, which is assigned to the assignee of the present application and is incorporated herein by reference, describes a method for facilitating a diagnosis of a condition of a subject, including applying a current to a site of the subject, such as the SPG, and configuring the current to increase conductance of molecules from brain tissue of the subject through a blood brain barrier (BBB) of the subject into a systemic blood circulation of the subject. The method also includes sensing a quantity of the molecules from a site outside of the brain of the subject, following initiation of application of the current.

US Patent Application Publication 2005/0266099 to Shalev, which is assigned to the assignee of the present application and is incorporated herein by reference, describes a method for modifying a property of a brain of a patient includes presenting an odorant to an air passage of the patient, the odorant having been selected for presentation to the air passage because it is such as to increase conductance of molecules from a systemic blood circulation of the patient through a blood brain barrier (BBB) of the brain into brain tissue of the patient. The molecules are selected from the group consisting of: a pharmacological agent, a therapeutic agent, an endogenous agent, and an agent for facilitating a diagnostic procedure.

PCT Publication WO 04/010923 to Gross et al., which is assigned to the assignee of the present application and is incorporated herein by reference, describes a chemical agent delivery system, including a chemical agent supplied to a body of a subject for delivery to a site in a central nervous system of said subject via blood of said subject; and a stimulator for stimulating parasympathetic fibers associated with the SPG, thereby rendering a blood brain barrier (BBB) of said subject permeable to said chemical agent during at least a portion of the time that said chemical agent is present in said blood.

PCT Publication WO 04/043218 to Gross et al., which is assigned to the assignee of the present application and is incorporated herein by reference, describes apparatus for treating a subject, including (a) a stimulation device, adapted to be implanted in a vicinity of a site selected from the list consisting of: a SPG and a neural tract originating in or leading to the SPG; and (b) a connecting element, coupled to the stimulation device, and adapted to be passed through at least a portion of a greater palatine canal of the subject.

PCT Publication WO 04/045242 to Shalev, which is assigned to the assignee of the present application and is incorporated herein by reference, describes apparatus for treating a condition of an ear of a subject, comprising a stimulator adapted to stimulate at least one site of the subject, such as the SPG, at a level sufficient to treat the ear condition.

PCT Publication WO 05/030025 to Shalev et al., which is assigned to the assignee of the present application and is incorporated herein by reference, describes apparatus for treating a subject, including an elongated generally rigid support element having a length of at least 1.8 cm, and having a distal end. The apparatus also includes one or more electrodes fixed to the support element in a vicinity of the distal end thereof, and configured to be positioned in a vicinity of a site of the subject, such as the SPG, when the support element is inserted into a body of the subject, such that a portion of the support element remains outside of the body. The apparatus further includes a control unit, coupled to the support element, and adapted to drive the electrodes to apply an electrical current to the site, and to configure the current to increase cerebral blood flow (CBF) of the subject, so as to treat a condition of the subject.

U.S. Pat. No. 6,526,318 to Ansarinia and related PCT Publication WO 01/97905 to Ansarinia, which are incorporated herein by reference, describe a method for the suppression or prevention of various medical conditions, including pain, movement disorders, autonomic disorders, and neuropsychiatric disorders. The method includes positioning an electrode on or proximate to at least one of the patient's SPG, sphenopalatine nerves, or vidian nerves, and activating the electrode to apply an electrical signal to such nerve. In a further embodiment for treating the same conditions, the electrode used is activated to dispense a medication solution or analgesic to such nerve.

U.S. Pat. No. 6,405,079 to Ansarinia, which is incorporated herein by reference, describes a method for the suppression or prevention of various medical conditions, including pain, movement disorders, autonomic disorders, and neuropsychiatric disorders. The method includes positioning an electrode adjacent to or around a sinus, the dura adjacent a sinus, or falx cerebri, and activating the electrode to apply an electrical signal to the site. In a further embodiment for treating the same conditions, the electrode dispenses a medication solution or analgesic to the site.

U.S. Pat. No. 6,788,975 to Whitehurst et al., which is incorporated herein by reference, describes an implantable stimulator with at least two electrodes that is small enough to have the electrodes located adjacent to a nerve structure at least partially responsible for epileptic seizures. The nerve structure may include a trigeminal ganglion or ganglia, a trigeminal nerve, or a branch of a trigeminal nerve, a greater occipital nerve, lesser occipital nerve, third occipital nerve, facial nerve, glossopharyngeal nerve, or a branch of any of these neural structures. Electrical stimulation of such targets may provide significant therapeutic benefit in the management of epilepsy.

U.S. Pat. No. 5,716,377 to Rise et al., which is incorporated herein by reference, describes techniques for stimulating the brain to treat movement disorders resulting in abnormal motor behavior by means of an implantable signal generator and electrode. A sensor is used to detect the symptoms resulting from the motion disorder. A microprocessor algorithm analyzes the output from the sensor in order to regulate the stimulation delivered to the brain.

U.S. Pat. No. 6,415,184 to Ishikawa et al., which is incorporated herein by reference, describes a ball semiconductor for stimulating a mass of nervous system brain tissue for therapeutic purposes. The ball is embedded in a mass of nervous system tissue of a brain. Electrical pulses generated and transmitted to the ball by a remote electrical pulse generator system are picked up by a receiving antenna of the ball, and are applied to an electrode pair of the ball to cause the mass of nervous system tissue of the brain located between output pads of the electrode to become stimulated, as therapy for a pathological condition, such as epilepsy.

U.S. Pat. No. 6,606,521 to Paspa et al., which is incorporated herein by reference, describes an implantable medical lead having markings, which aid in the accurate localization of lead electrodes at a specific point of the brain for neurostimulation. Also described is an implantable medical lead having a removable extension that provides a minimal length of excess lead protruding from the lead insertion site. The lead and method of implantation facilitate use of a neurostimulator device that is implanted directly in a patient's cranium.

U.S. Pat. No. 6,591,138 to Fischell et al., which is incorporated herein by reference, describes a system for treating neurological conditions by low-frequency time varying electrical stimulation. The system includes an electrical device for applying such low-frequency energy, in a range below approximately 10 Hz, to the patient's brain tissue. An implantable embodiment applies direct electrical stimulation to electrodes implanted in or on the patient's brain, while a non-invasive embodiment causes a magnetic field to induce electrical currents in the patient's brain.

U.S. Pat. No. 6,343,226 to Sunde et al., which is incorporated herein by reference, describes a quadripolar deep brain stimulation electrode for treating symptoms of central and peripheral nervous system disorders, such as Parkinson's disease, epilepsy, psychiatric illness, and intractable pain. It is important to determine the optimal placement of an implanted electrode. An electrode device is described that allows stimulation of a large volume of neural tissue in combination with simultaneous microelectrode recording. The device is described as allowing for a less traumatic localization of the optimal neural stimulation area by microelectrode recording in combination with the placement of the permanent deep brain stimulation electrode.

US Patent Application Publication 2005/0065427 to Magill et al., which is incorporated herein by reference, describes a method for locating the position of a selected neural center in the central nervous system, including stimulating neurons at a first central nervous system position, measuring the field potential evoked at a second central nervous system position, and comparing the evoked field potential against a known evoked field potential from said neural center.

US Patent Application Publication 2005/0113877 to Spinelli et al., which is incorporated herein by reference, describes implantable devices and methods for treating various disorders of the pelvic floor by means of electrical stimulation of the pudendal or other nerves. Neurophysiological monitoring is utilized to assess the evoked responses of the pudendal nerve, and thereby to provide a method for determining the optimal stimulation site.

U.S. Pat. No. 5,314,495 to Kovacs, which is incorporated herein by reference, describes a microelectrode interface for localizing the stimulation and recording of action potentials at a portion of a nervous system. A circuit is described for applying current only to one or more selected pairs of microelectrodes in an array of microelectrodes. Row and column select lines, switches and multiplexes are used for passing current only between pairs of microelectrodes at selected locations in the array for stimulating a portion of a nervous system only at selected locations.

U.S. Pat. No. 6,432,986 to Levin and PCT Publication WO 99/03473 to Levin, which are incorporated herein by reference, describe techniques for inhibiting a cerebral neurovascular disorder or a muscular headache. The techniques include intranasally administering a pharmaceutical composition comprising a long-acting local anesthetic.

U.S. Pat. No. 6,491,940 to Levin, US Patent Application 2003/0133877 to Levin, and PCT Publication WO 00/44432 to Levin, which are incorporated herein by reference, describe techniques for inhibiting a cerebral neurovascular disorder or a muscular headache. The techniques include intranasally administering a pharmaceutical composition comprising a long-acting local anesthetic. Apparatus for delivering or applying the composition is also described.

US Patent Application 2001/0004644 to Levin and PCT Publication WO 01/43733 to Levin, which are incorporated herein by reference, describe techniques for inhibiting cephalic inflammation, including meningeal inflammation and cerebral inflammation. The techniques include intranasally administering a long-acting local anesthetic. Apparatus for delivering or applying the composition is also described, including a dorsonasally implanted electronic neural stimulator, such as a transepithelial neural stimulation device.

The following patents and patent application publications, all of which are incorporated herein by reference, may be of interest: U.S. Pat. No. 5,756,071 to Mattern et al., U.S. Pat. No. 5,752,515 to Jolesz et al., PCT Publications WO 03/084591, WO 03/020350, WO 03/000310, WO 02/068031, and WO 02/068029 to Djupesland, US Patent Application Publication 2003/0079742 to Giroux, U.S. Pat. Nos. 5,725,471 and 6,086,525 to Davey et al., PCT Publication WO 02/32504 to Zanger et al., US Patent Application Publication 2003/0050527 to Fox et al., U.S. Pat. No. 6,432,986 to Levin, PCT Publication WO 99/03473 to Levin, U.S. Pat. No. 6,491,940 to Levin, US Patent Application 2003/0133877 to Levin, and PCT Publication WO 00/44432 to Levin, US Patent Application 2001/0004644 to Levin, PCT Publication WO 01/43733 to Levin, U.S. Pat. No. 4,867,164 to Zabara, U.S. Pat. Nos. 6,341,236 and 6,671,556 to Osorio et al., U.S. Pat. No. 6,671,555 to Gielen et al., U.S. Pat. No. 5,978,702 to Ward et al., U.S. Pat. No. 6,205,359 to Boveja, U.S. Pat. No. 6,470,212 to Weijand et al., U.S. Pat. No. 6,640,137 to MacDonald, U.S. Pat. No. 6,735,475 to Whitehurst et al., PCT Publication WO 01/97906 to Whitehurst, U.S. Pat. No. 6,922,590 to Whitehurst, PCT Publication WO 05/062829 to Whitehurst et al., and US Patent Application Publication 2005/0154419 to Whitehurst et al.

Hotta H et al., in an article entitled, “Effects of stimulating the nucleus basalis of Meynert on blood flow and delayed neuronal death following transient ischemia in rat cerebral cortes,” Jap J Phys 52:383-393 (2002), which is incorporated herein by reference, report that stimulation of the nucleus basalis of Meynert (NBM) in the rat was accompanied by vasodilatation and increase in cortical blood flow. They suggest that NBM-originating vasodilative activation can protect the ischemia-induced delayed death of cortical neurons by preventing a blood flow decrease in widespread cortices.

Reis D J et al., in an article entitled, “Electrical stimulation of cerebellar fastigial nucleus reduces ischemic infarction elicited by middle cerebral artery occlusion in rat,” J Cereb Blood Flow Metab 11(5):810-8 (1991), which is incorporated herein by reference, report that electrical stimulation of the cerebellar fastigial nucleus (FN) profoundly increases cerebral blood flow via a cholinergic mechanism. Utilizing the rat middle cerebral artery occlusion (MCAO) model, they demonstrated that one hour of electrical stimulation of the FN has the capacity to substantially reduce the infarct size at the rim of the cortex dorsal and ventral to the infarction, and medially within the thalamus and striatum corresponding to the penumbral zone. They conclude that excitation of an intrinsic system in brain represented in the rostral FN has the capacity to substantially reduce an ischemic infarction.

Matsui T et al., in an article entitled, “The effects of cervical spinal cord stimulation (cSCS) on experimental stroke,” Pacing Clin Electrophysiol 12(4 Pt 2):726-32 (1989), which is incorporated herein by reference, report that cSCS increases regional cerebral blood flow, and, in a cat middle cerebral artery occlusion model (MCAO), reduced the rate of death within 24 hours after MCAO.

Segher O et al., in an article entitled, “Spinal cord stimulation reducing infract volume in model of focal cerebral ischemia in rats,” J Neurosurg 99(1):131-137 (2003), which is incorporated herein by reference, demonstrate that spinal cord stimulation increases cerebral blood flow in rats and significantly reduces stroke volume, suggesting that spinal cord stimulation could be used for treatment and prevention of stroke.

The following references, which are incorporated herein by reference, may be useful:

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SUMMARY OF THE INVENTION

In some embodiments of the present invention, a neural stimulation system comprises an implantable neural stimulator, an oral element, and an external control unit. The neural stimulator comprises an elongated support element, one or more electrodes fixed to the support element in a vicinity of a distal end thereof, and a wireless coupling element physically attached to the support element, e.g., in a vicinity of a proximal end thereof. The stimulator is adapted to be passed through a greater palatine foramen of a palate of an oral cavity of a subject into a greater palatine canal, such that the electrodes are brought into a vicinity of a sphenopalatine ganglion (SPG). For some applications, the stimulator comprises a locking element, which is adapted to hold the stimulator in place after implantation.

In some embodiments of the present invention, the distal end of the support element comprises a surgical punch, which enables the stimulator to be passed through the palate in a minimally-invasive procedure, without requiring a prior surgical incision in the mucosa. The wireless coupling element is sufficiently small so as to be able to pass through the punch incision without requiring the incision to be surgically enlarged. The use of the punch to insert the stimulator, rather than a more complicated surgical procedure, generally allows the stimulator to be quickly implanted in the subject.

The oral element of the system is adapted to be placed in the oral cavity, e.g., in a vicinity of or in contact with the roof of the oral cavity or the alveolar process of the maxilla, in a vicinity of the implanted wireless coupling element of the stimulator. The oral element comprises a power source, such as a rechargeable or disposable battery, and at least one wireless coupling element. The wireless coupling element of the oral element is adapted to wirelessly transmit energy to the wireless coupling element of the stimulator, for powering the stimulator. For some applications, the wireless coupling element of the oral element is additionally configured to transmit and/or receive data to/from the wireless coupling element of the stimulator. For some applications, the oral element transmits/receives data to/from the external control unit. Alternatively, the stimulator transmits/receives data directly to/from the external control unit.

In some embodiments of the present invention, a neural stimulation system comprises an implantable neural stimulator and an external control unit. The neural stimulator comprises an elongated support element, one or more electrodes fixed to the support element in a vicinity of a distal end thereof, and an implantable antenna coupled to the support element in a vicinity of a proximal end thereof. The support element is adapted to be passed through a palate of an oral cavity of a subject into a greater palatine canal, such that the electrodes are brought into a vicinity of a SPG. For some applications, the implantable antenna comprises a submucosal antenna comprising a thin, flexible sheet comprising at least one coil. The submucosal antenna is adapted to be implanted in the roof of the oral cavity between the oral mucosa and the palate, e.g., the hard palate, and to conform to the shape of the palate. For other applications, the implantable antenna comprises a coil antenna, which is coiled around at least a portion of the support element. In these embodiments, the system typically lacks an oral element. Instead, the external control unit is adapted to transmit power directly (typically as radiofrequency (RF) energy) to the submucosal antenna of the stimulator, and to transmit and/or receive data directly to/from the submucosal antenna. Typically, the external control unit is adapted to be placed in a vicinity of a head of the subject, such as in a vicinity of an ear of the subject, e.g., coupled to the ear.

In some embodiments of the present invention, the one or more electrodes of the stimulator comprise an array of electrodes, at least a portion of which are adapted to be separately activatable. After the stimulator has been implanted, the stimulation system uses a calibration algorithm to activate, during a plurality of calibration periods, respective different sets of one or more of the electrodes, in order to determine which set's activation causes a level of stimulation of the SPG closest to a desired level. Use of such an algorithm generally obviates the need to adjust the location of the stimulator after it has been implanted. For some applications, the level of stimulation of the SPG is determined by receiving feedback directly from the SPG, or from other neural tissue in a vicinity of the SPG, i.e., by using at least a portion of the electrodes to directly measure a level of stimulation of the SPG or the other neural tissue at or in a vicinity of the site(s) of the stimulation by the electrodes. Alternatively, the level of stimulation of the SPG is determined by assessing an indirect physiological parameter of the subject related to the level of SPG stimulation, such as cerebral blood flow (CBF).

In some embodiments of the present invention, the elongated support element of the stimulator has a length of between about 1.8 and about 4 cm, such as between about 1.8 cm and about 3 cm, e.g., between about 2.6 and about 3 cm, such as about 2.8 cm, and/or has a curvature that follows that of the greater palatine canal.

For some applications, treatment with the systems described herein is applied as soon as possible after diagnosis of the condition, such as in an emergency room or wherever the subject happens to be. For other applications, the system is appropriate for longer-term treatment, such as for modulating the permeability of the BBB, modulating cerebral blood flow (CBF), rehabilitation after brain events, or prevention and/or treatment of epilepsy. For some applications, the stimulator is adapted to be implanted for at least one week, e.g., at least one month, while for other applications, the stimulator is adapted to be implanted for less than one week, e.g., less than one day.

In some embodiments of the present invention, an electrical stimulator drives current into at least one “modulation target site” (MTS), as defined hereinbelow. Typically, the stimulator drives the current in order to control and/or modify SPG-related behavior, e.g., in order to induce changes in cerebral blood flow and/or to modulate permeability of the blood-brain barrier (BBB). Concurrently with or after placement of the stimulator near or in contact with an MTS, at least one physiological indicator of cerebral blood flow (CBF) is observed or measured. Optimization of placement of the stimulator onto the appropriate neural structure is performed by activating the stimulator, and generally simultaneously monitoring CBF while manipulating the placement of the stimulator so as to increase or decrease CBF, as appropriate. Alternatively or additionally, a similar optimization process is performed, either during or after implantation of the stimulator, to determine parameters of the applied current that achieve a desired effect, as indicated by CBF.

In some embodiments of the present invention, an electrical stimulation system is provided for the treatment of an adverse brain condition, such as an adverse cerebrovascular condition, e.g., an ischemic event. The system is configured to apply excitatory electrical stimulation to at least one “modulation target site” (MTS), as defined hereinbelow, such as a sphenopalatine ganglion (SPG). The system configures the stimulation to dilate cerebral vessels, thereby increasing cerebral blood flow (CBF) to affected brain tissue and tissue in a vicinity thereof, and/or to induce the release of one or more neuroprotective substances, such as neuromodulators (e.g., nitric oxide (NO) and/or vasoactive intestinal polypeptide (VIP)). Such increased CBF and/or release of neuroprotective substances decreases damage caused by the brain condition. The stimulation system is generally useful for treating brain ischemia, such as caused by ischemic stroke or other brain conditions.

For some applications, the system is configured to perform acute treatment of an adverse cerebrovascular event, such as ischemic stroke, by applying the stimulation within three hours of the stroke, while a significant penumbra remains. Experiments conducted by the inventors have demonstrated the efficacy of such acute treatment in an animal model. For other applications, the system is configured to perform post-acute treatment of ischemic stroke, by applying the stimulation more than three hours after the stroke, when a significant penumbra generally no longer remains. Experiments conducted by the inventors have demonstrated the efficacy of such post-acute treatment in an animal model. For still other applications, the system is configured to apply stimulation on a chronic, long-term basis, for at least one week, such as at least two weeks, at least four weeks, at least three months, or at least six months. During this chronic treatment, stimulation is typically applied intermittently, such as during one session per day. Experiments conducted by the inventors have demonstrated the efficacy of such post-acute treatment in an animal model.

In some embodiments of the present invention, the system is configured to perform staged treatment of an adverse brain event, such as a cerebrovascular event, e.g., an ischemic stroke. The system is configured to adjust at least one parameter of the applied stimulation responsively to an amount of time that has elapsed since the occurrence of the brain condition. For some applications, during a first, acute stage, the system sets the parameters of stimulation at a first, high level, which is sufficient to cause a high level of cerebral vessel dilation and/or a release of neuroprotective substances, but insufficient to induce a significant increase in permeability of the blood-brain barrier (BBB). Such stimulation is primarily intended to arrest the spreading of the initial ischemic core, such as by restoring blood flow to the penumbra in order to prevent damage to cells therein, and/or by releasing neuroprotective substances, such as NO and/or VIP. Such stimulation may also save some cells within the ischemic core, such as neuronal cells. The first stage of stimulation is typically appropriate during the period beginning at the time of the event, and ending at about 4 to 8 hours after the time of the event, such as at about 6 hours after the event. Alternatively, the first stage of stimulation is appropriate until about 24 hours after the time of the event.

During a second, rehabilitative stage, the system reduces the strength of the stimulation, and typically applies the stimulation intermittently, such as during one session per day, having a duration of between about 2 and about 3 hours. (For some applications, the session has a shorter duration, e.g., between about 0.5 and about 2 hours, or a longer duration, e.g., between about 3 and about 16 hours.) This rehabilitative level of stimulation generally continues to induce the release of neuroprotective substances, and/or maintains a slightly elevated level of blood flow to the brain. This stage of stimulation is typically applied during the period beginning at the conclusion of the first stage, and lasting at least one week, such as at least two weeks, at least one month, at least three months, or at least six months.

In the present patent application, a “modulation target site” (MTS) consists of:

-   -   an SPG (also called a pterygopalatine ganglion);     -   a nerve of the pterygoid canal (also called a vidian nerve),         such as a greater superficial petrosal nerve (a preganglionic         parasympathetic nerve) or a lesser deep petrosal nerve (a         postganglionic sympathetic nerve);     -   a greater palatine nerve;     -   a lesser palatine nerve;     -   a sphenopalatine nerve;     -   a communicating branch between the maxillary nerve and the         sphenopalatine ganglion;     -   an otic ganglion;     -   an afferent fiber going into the otic ganglion;     -   an efferent fiber going out of the otic ganglion; or     -   an infraorbital nerve.

In some embodiments of the present invention, an electrical stimulation system is configured to apply excitatory electrical stimulation to at least one MTS of a subject, and to configure the stimulation to increase CBF of the subject and/or induce the release of one or more neuroprotective substances, such as neuromodulators (e.g., nitric oxide (NO) and/or vasoactive intestinal polypeptide (VIP)), without significantly opening the BBB of the subject. For some applications, the system sets a strength of the stimulation to less than 90% of the minimum strength necessary to begin significantly opening the BBB (the “minimum BBB-opening strength”), such as less than about 80%, about 70%, or about 60% of the minimum BBB-opening strength. For some applications, the system sets the strength of stimulation to a level appropriate for long-term rehabilitation or prevention of a brain condition, such as between about 10% and about 40% of the minimum BBB-opening strength, e.g., between about 20% and about 30% of the minimum BBB-opening strength. For other applications, the system sets the strength of stimulation to a level appropriate for acute treatment of a brain event, such as at least about 20% of the minimum BBB-opening strength, e.g., at least about 50%, 60%, 70%, or 80% of the minimum BBB-opening strength.

In some embodiments of the present invention, a method for treating a brain tumor comprises: (a) during a first period of time, applying excitatory electrical stimulation to at least one MTS at a first, relatively low strength, in conjunction with administration of a chemotherapeutic drug at a first, relatively high dosage; and (b) during a second period of time after the first period, applying the stimulation at a second strength greater than the first strength, in conjunction with administration of the drug at a second dosage lower than the first dosage. Typically, stimulation at the first strength is sufficient to open the blood-tumor barrier (BTB) in the core and tissue near the core of the tumor, where the BTB has generally been damaged, but not in the periphery of the tumor, where the BBB/BTB generally remains substantially intact. Stimulation at the second strength is typically sufficient to open the BBB in the periphery of the tumor and throughout the brain.

In some embodiments of the present invention, the cerebrovascular condition is caused by a cerebrovascular incident, such as stroke, aneurysm, or an arteriovenous malformation, or by an anoxic/hypoxic/ischemic event, such as anoxic brain injury caused by near drowning, kidney failure, heart failure, chemical exposure, myocardial infarction, or electric shock. As used in the present application, including in the claims, the phrase an “adverse cerebrovascular event” includes, but is not limited to, a cerebrovascular incident, such as stroke, aneurysm, or an arteriovenous malformations, and an anoxic/hypoxic/ischemic event, such as anoxic brain injury caused by near drowning, kidney failure, heart failure, chemical exposure, myocardial infarction, or electric shock. As used in the present application, including in the claims, the phrases an “adverse cerebrovascular event” and an “adverse cerebrovascular condition” exclude from their scope Alzheimer's disease and Parkinson's disease. Nevertheless, in some embodiments of the present invention, at least some of the techniques described herein may be used for treating these two diseases.

In some embodiments of the present invention, chemical stimulation of at least one MTS is achieved by presenting chemicals, for example in a liquid or gaseous state, to an air passage of the subject, such as a nasal cavity or a throat, or in a vicinity thereof. The temporal profile and other quantitative characteristics of such chemical modulation are believed by the present inventors to have a mechanism of action that has a neuroanatomical basis overlapping with that of the electrical modulation of the MTS. For some applications, chemical-presentation techniques described herein are practiced in combination with techniques described in PCT Patent Application PCT/IL03/000338 (published as PCT Publication WO 03/090599), filed Apr. 25, 2003 and/or US Patent Application Publication 2005/0159790, both of which are assigned to the assignee of the present patent application and are incorporated herein by reference.

Chemicals that may increase or decrease cerebral blood flow and/or the permeability of the blood-brain barrier (e.g., via modulation of SPG-related fibers), include, but are not limited to, propionic acid, cyclohexanone, amyl acetate, acetic acid, citric acid, carbon dioxide, sodium chloride, ammonia, menthol, alcohol, nicotine, piperine, gingerol, zingerone, allyl isothiocyanate, cinnamaldehyde, cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate, thymol, and eucalyptol. The chemicals reach the appropriate neural structures and induce vasodilatation, vasoconstriction and/or cerebrovascular permeability changes.

In some embodiments of the present invention, chemical stimulation is applied to at least one MTS, using (a) a nasal applicator configured to deliver the stimulating chemical to an upper region of the nasal cavity, or (b) a transpalatine applicator inserted via the greater palatine canal.

In some embodiments of the present invention, stimulation of the MTS is achieved by applying mechanical stimulation to the MTS, e.g., vibration.

In some embodiments of the present invention, stimulation of at least one MTS is achieved by applying a neuroexcitatory agent to the MTS. Suitable neuroexcitatory agents include, but are not limited to, acetylcholine and urocholine. For some applications, the MTS is stimulated by applying a neuroinhibitory agent, such as atropine, hexamethonium, or a local anesthetic (e.g., lidocaine).

It is to be appreciated that references herein to specific modulation target sites are to be understood as including other modulation target sites, as appropriate.

It is further to be appreciated that insertion and modulation sites, methods of insertion and/or implantation, and parameters of modulation are described herein by way of illustration and not limitation, and that the scope of the present invention includes other possibilities which would be obvious to someone of ordinary skill in the art who has read the present patent application.

It is yet further to be appreciated that while some embodiments of the invention are generally described herein with respect to electrical transmission of power and electrical modulation of tissue, other modes of energy transport may be used as well. Such energy includes, but is not limited to, direct or induced electromagnetic energy, radiofrequency (RF) transmission, mechanical vibration, ultrasonic transmission, optical power, and low power laser energy (via, for example, a fiber optic cable).

It is additionally to be appreciated that whereas some embodiments of the present invention are described with respect to application of electrical currents to tissue, this is to be understood in the context of the present patent application and in the claims as being substantially equivalent to applying an electrical field, e.g., by creating a voltage drop between two electrodes.

In embodiments of the present invention, treating an adverse brain event or condition typically includes identifying that a subject is suffering from, and/or has suffered from, the brain event or condition.

In some embodiments of the present invention, magnetic stimulation is applied to at least one MTS using a magnetic induction device that comprises a control unit, and at least one coil that is adapted to be placed in a vicinity of the MTS. For some applications, e.g., in which the MTS includes an SPG of the subject, the coil is adapted to be inserted into a nasal cavity of the subject. Alternatively, the coil is adapted to be placed in a vicinity of a temporomandibular joint, in a vicinity of the MTS. Further alternatively, the coil is adapted to be placed completely or partially around the head, and to focus the magnetic field on the MTS.

There is therefore provided, in accordance with an embodiment of the present invention, apparatus for application to a subject, including:

an elongated support element having a length of between 1.8 cm and 4 cm, and having proximal and distal ends; one or more electrodes fixed to the support element in a vicinity of the distal end thereof, and adapted to apply an electrical current to a sphenopalatine ganglion (SPG) of the subject; a receiver, fixed to the support element, and electrically coupled to the electrodes; and a wireless transmitter, adapted to be placed in an oral cavity of the subject, and to be wirelessly coupled to the receiver.

For some applications, the wireless transmitter is adapted to be electromagnetically coupled to the receiver, or wirelessly coupled to the receiver via ultrasound. Alternatively, the receiver is adapted to be wireless coupled to the wireless transmitter by induction. For some applications, the electrodes are adapted to apply the current using only power received by the receiver from the wireless transmitter.

For some applications, the apparatus includes an oral appliance, adapted to be fixed to the transmitter, and shaped so as to define a surface that fits closely to a roof of the oral cavity. Alternatively, the apparatus includes an oral appliance, adapted to be fixed to the transmitter, and adapted to be coupled to a tooth of the subject, and/or adapted to be coupled to gingival covering an alveolar process of the subject.

For some applications, the apparatus includes an oral appliance, which includes: a capsule, which is configured to be placed and held between an alveolar process and an inner surface of a cheek of the subject; the transmitter; and an elongated coupling element, which couples the transmitter to the capsule. For some applications, the transmitter is adapted to be implanted in a tooth of the subject. For some applications, at least a portion of the receiver is adapted to be positioned between mucosa and a hard palate of the subject. Alternatively, at least a portion of the receiver is adapted to be positioned between mucosa and an alveolar process of a maxilla of the subject.

For some applications, the apparatus includes one or more electrode leads, which electrically couple the receiver to the electrodes, and which serve as the support element. For some applications, the distal end of the support element includes a surgical punch.

In an embodiment, the apparatus includes an external control unit, adapted to be placed outside of a head of the subject, which includes a control unit wireless coupling element, which is adapted to wirelessly transmit data from the control unit to the receiver.

For some applications, the electrodes include exactly one cathode and exactly one anode, and a closest distance between the cathode and the anode is greater than a closest distance between any portion of the cathode and any portion of the SPG when the electrodes are positioned in a vicinity of the SPG.

For some applications, the support element, electrodes, and receiver are adapted to be implanted in the subject for at least one week. Alternatively, the support element, electrodes, and receiver are adapted to be implanted in the subject for less than one day.

For some applications, the support element is sufficiently rigid to enable insertion of the support element into a body of the subject by pushing from a vicinity of the proximal end of the support element.

For some applications, the support element has a curvature that follows that of a greater palatine canal of the subject.

In an embodiment, the receiver is fixed to the support element in a vicinity of the proximal end of the support element. For some applications, the apparatus includes a circuit module, which is fixed to the proximal end of the support element, and which includes a printed circuit board and the receiver. For some applications, the circuit module includes one or more layers of coating applied thereto.

For some applications, the support element is folded in a vicinity of the proximal end of the support element, at an angle approximately equal to an angle between a greater palatine canal of the subject and a hard palate of the subject in a vicinity of a greater palatine foramen of a subject, and the circuit module is adapted to be placed submucosally against a lower surface of the hard palate.

Alternatively, the proximal end of the support element is fixed to the circuit module such that an angle between the support element and a surface of the circuit module is approximately equal to an angle between a greater palatine canal of the subject and a hard palate of the subject in a vicinity of a greater palatine foramen of a subject, and the circuit module is adapted to be placed submucosally against a lower surface of the hard palate. For some applications, the proximal end of the support element is fixed to the circuit module in a vicinity of a center of the surface of the circuit module, or in a vicinity of an edge of the surface of the circuit module.

For some applications, the proximal end of the support element is fixed to the circuit module in a vicinity of an edge of the circuit module, and the circuit module is adapted to be placed submucosally against an alveolar process of a maxilla of the subject.

In an embodiment, the apparatus includes: an external control unit, adapted to be placed outside of a head of the subject, the external control unit including a control unit wireless coupling element; a support element wireless coupling element, coupled to the support element; and circuitry, coupled to the support element, and adapted to drive the wireless coupling element to wirelessly transmit feedback information to the external control unit. For some applications, the support element wireless coupling element and the receiver include a common transducer element.

In an embodiment, the apparatus includes: an oral element, which includes the wireless transmitter; an external driver, which includes a power source and circuitry, and which is adapted to be placed outside a body of the subject; and one or more wires which electrically couple the external driver to the oral element. For some applications, the external driver is adapted to be physically coupled to the body of the subject. For some applications, the apparatus includes an external control unit, which is adapted to be placed outside the body of the subject, and which is coupled to the external driver.

In an embodiment, the apparatus includes an oral element, which includes the wireless transmitter and oral element circuitry coupled to the wireless transmitter; and a power source, adapted to provide power to the wireless transmitter and circuitry. For some applications, the oral element includes the power source. Alternatively, the power source is adapted to be placed outside a body of the subject, and to be coupled to the oral element. For some applications, the apparatus includes receiver circuitry, which is coupled to the support element and the receiver, and the oral element circuitry is adapted to drive the wireless transmitter to transmit energy that does not include a stimulation waveform for application by the electrodes, the receiver is adapted to receive the energy, and the receiver circuitry is adapted to generate the stimulation waveform using the energy, and to drive the electrodes to apply the stimulation waveform to the SPG.

For some applications, the apparatus includes receiver circuitry, which is coupled to the support element and the receiver, and the oral element circuitry is adapted to drive the wireless transmitter to transmit energy that includes a stimulation waveform for application by the electrodes, the receiver is adapted to receive the energy, and the receiver circuitry is adapted to drive the electrodes to apply the stimulation waveform to the SPG.

For some applications, the oral element is adapted to be fixed to a roof of the oral cavity. Alternatively, the oral element is adapted to temporarily placed against the roof of the oral cavity, without being fixed thereto.

For some applications, the apparatus includes an external control unit, adapted to be placed outside of a head of the subject, the external control unit including a control unit wireless coupling element, which is adapted to wirelessly transmit data from the control unit to the oral element, and the oral element is adapted to wirelessly transmit the received data to the receiver. For some applications, the oral element is adapted to wirelessly transmit feedback information to the external control unit.

In an embodiment, the support element has a length of between 1.8 and 3 cm, such as between 2.6 and 3 cm.

In an embodiment, at least a portion of the support element is adapted to be placed in a greater palatine canal of the subject. For some applications, the support element includes a lock, adapted to hold the support element in place after insertion thereof into the greater palatine canal. For some applications, the support element is adapted to be inserted into the greater palatine canal such that no portion of the support element protrudes into the oral cavity. For example, the receiver may be adapted to be contained entirely within the greater palatine canal when the support element is inserted into the greater palatine canal. For some applications, the receiver includes at least one coil that is coiled around at least a portion of the support element. For some applications, the at least one coil includes a plurality of coils which are oriented in a plurality of respective orientations.

For some applications, the apparatus includes circuitry adapted to measure, using at least one of the electrodes, a level of stimulation induced by the applied current, such as a level of stimulation of the SPG.

For some applications, the one or more electrodes include a plurality of electrodes, and the apparatus includes circuitry adapted to perform a calibration procedure by activating, during a plurality of calibration periods, respective different sets of one or more of the electrodes. For some applications, the circuitry is adapted to measure, during each of the calibration periods, using at least one of the electrodes, an indication of a level of stimulation induced by the activation of the respective set of electrodes, such as a level of stimulation of the SPG.

There is further provided, in accordance with an embodiment of the present invention, apparatus for application to a subject, including:

one or more electrodes adapted to apply an electrical current to tissue of the subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; a receiver, electrically coupled to the one or more electrodes; and a wireless transmitter, adapted to be placed in an oral cavity of the subject, and to be wirelessly coupled to the receiver.

In an embodiment, the tissue includes the SPG, and the one or more electrodes are adapted to apply the current to the SPG.

For some applications, the wireless transmitter is adapted to be electromagnetically coupled to the receiver, or wirelessly coupled to the receiver via ultrasound. Alternatively, the receiver is adapted to be wirelessly coupled to the wireless transmitter by induction.

For some applications, the apparatus includes an oral appliance, adapted to be fixed to the transmitter, and shaped so as to define a surface that fits closely to a roof of the oral cavity.

There is also provided, in accordance with an embodiment of the present invention, apparatus for application to a subject, including:

an elongated support element adapted to be placed within a greater palatine canal of the subject, sized to extend from a palate of the subject to a sphenopalatine ganglion (SPG) of the subject, and having distal and proximal ends; and one or more electrodes fixed to the support element in a vicinity of the distal end thereof; and a control unit, coupled to the electrodes, and adapted to drive the electrodes to apply an electrical current to the SPG.

In an embodiment, the support element is adapted to have a length that is adjustable during an implantation procedure. For some applications, the support element includes at least two portions that are telescopically coupled to one another. For some applications, the apparatus includes a sleeve, which surrounds a portion of the support element. For some applications, a portion of the support element is shaped so as to define one or more accordion pleats. For some applications, the apparatus includes one or more electrode leads coupled to the electrodes, which leads serve as the support element and are accordion-pleated, a portion of which leads are helically wound so as to form a spring, or which leads are shaped so as to define at least one omega-shaped portion.

In an embodiment, the support element includes a support element electrical contact in a vicinity of the proximal end thereof, the control unit includes a control unit electrical contact, and the control unit is adapted to be placed in an oral cavity of the subject such that the control unit electrical contact is brought into physical contact with the support element electrical contact, thereby coupling the control unit to the electrodes. For some applications, the control unit is adapted to temporarily placed against a roof of the oral cavity, without being fixed thereto. For some applications, the control unit is adapted to be fixed to a roof of the oral cavity. For some applications, the support element electrical contact is adapted to be in sealed contact with mucosa of the subject. Alternatively or additionally, the support element electrical contact includes a matrix, which is adapted to promote mucosal tissue growth therein.

In an embodiment, the apparatus includes a receiver, which is fixed to the support element; and a wireless transmitter, which is coupled to the control unit, and which is adapted to be wirelessly coupled to the receiver, thereby coupling the control unit to the electrodes. For some applications, the wireless transmitter is adapted to be placed in an oral cavity of the subject. Alternatively, the wireless transmitter is adapted to be placed outside of a head of the subject. For some applications, the apparatus includes an autonomically-powered power supply physically coupled to the support element, which is adapted to provide power for the electrodes, and the control unit is adapted to wirelessly transmit data to the receiver.

There is additionally provided, in accordance with an embodiment of the present invention, apparatus including an implantable neural stimulator, which includes:

one or more electrodes adapted to be placed in a vicinity of a greater palatine foramen of a subject; and a control unit, coupled to the electrodes, and adapted to drive the electrodes to apply an electrical current to a greater palatine nerve of the subject.

For some applications, the electrodes are adapted to be placed within 5 mm of the greater palatine foramen. For some applications, the electrodes are adapted to be contained entirely within a greater palatine canal of the subject. For some applications, at least a portion of the electrodes is adapted to be located between mucosa and a palate of the subject.

There is yet additionally provided, in accordance with an embodiment of the present invention, apparatus including an implantable neural stimulator, which includes:

one or more electrodes adapted to apply an electrical current to tissue of a subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; an implantable submucosal antenna, which includes at least one coil, and is adapted to be implanted between oral mucosa and a palate of the subject; and one or more electrode leads, which electrically couple the submucosal antenna to the electrodes.

In an embodiment, the tissue includes the SPG, and the one or more electrodes are adapted to apply the current to the SPG.

In an embodiment, the submucosal antenna includes a flexible sheet, which includes the at least one coil.

For some applications, the apparatus includes an external driver, which includes a power source and circuitry, which is adapted to be placed outside a body of the subject, and which is adapted to be wirelessly coupled to the submucosal antenna; and an external control unit, which is adapted to be placed outside the body of the subject, and which is coupled to the external driver.

In an embodiment, the stimulator includes an elongated support element having proximal and distal ends, which is adapted to be inserted into a greater palatine canal of the subject, and the one or more electrodes are coupled to the support element in a vicinity of the distal end, and the submucosal antenna is coupled to the support element in a vicinity of the proximal end. For some applications, the support element has a length of between 2.6 cm and 3 cm. For some applications, the support element is adapted to have a length that is adjustable during an implantation procedure.

In an embodiment, the apparatus includes a control unit, adapted to be wirelessly coupled to the submucosal antenna. For some applications, the control unit is adapted to transmit power and data to the submucosal antenna, and the stimulator is adapted to use the power to generate a stimulation waveform at least in part responsively to the received data, and to drive the one or more electrodes to apply the stimulation waveform. For some applications, the control unit is adapted to be placed externally to a body of the subject, such as in a vicinity of a head of the subject, e.g., in a vicinity of an ear of the subject.

There is still additionally provided, in accordance with an embodiment of the present invention, apparatus including an implantable neural stimulator, which includes:

a plurality of electrodes adapted to apply an electrical current to a site of a subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; and a control unit, coupled to the electrodes, and adapted to perform a calibration procedure by activating, during a plurality of calibration periods, respective different sets of one or more of the electrodes.

For some applications, the control unit is adapted to be placed externally to a body of the subject, and to be wirelessly coupled to the electrodes.

In an embodiment, the control unit is adapted to receive, during each of the calibration periods, an indication of a level of stimulation induced by the activation of the respective set of electrodes, such as a level of stimulation of the site. For some applications, the control unit is adapted to select the set of electrodes the activation of which induced the level of stimulation nearest a desired level of stimulation.

For some applications, the control unit is adapted to receive the indication of the level of stimulation, e.g., of the site, by using at least a portion of the electrodes to measure the level of stimulation. For some applications, the control unit is adapted to measure, using the at least a portion of the electrodes, an electric field of nervous tissue, e.g., of the site, induced by the activation of the respective set of electrodes. For some applications, the at least a portion of the electrodes includes one or more of the electrodes of the respective set of electrodes. For some applications, the at least a portion of the electrodes includes one or more of the electrodes positioned in a vicinity of the electrodes of the respective set of electrodes.

For some applications, the indication includes an indirect physiological parameter of the subject related to the level of the stimulation, and the control unit is adapted to receive the indirect physiological parameter during each of the calibration periods. For some applications, the indirect physiological parameter includes an indication of cerebral blood flow (CBF) of the subject, and the control unit is adapted to receive the indication of CBF. For some applications, the indirect physiological parameter includes an indication of blood-brain barrier (BBB) permeability of the subject, and the control unit is adapted to receive the indication of BBB permeability. For some applications, the apparatus includes a device adapted to measure the indirect physiological parameter, and the control unit is adapted to receive the indirect physiological parameter measured by the device.

In an embodiment, the site includes the SPG, and the electrodes are adapted to apply the current to the SPG. For some applications, the stimulator includes an elongated support element having a distal end, and adapted to be inserted into a greater palatine canal of the subject via a palate of the subject, and the electrodes are coupled to the support element in a vicinity of the distal end.

There is still further provided, in accordance with an embodiment of the present invention, apparatus including an implantable neural stimulator, which includes:

a set of one or more electrodes adapted to be placed in a vicinity of a site of a subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; and a control unit, coupled to the set of electrodes, and adapted to: drive at least one of the electrodes to apply an electrical current to the site, and using at least one of the electrodes, measure a level of stimulation induced by the applied current.

In an embodiment, the level of stimulation includes a level of stimulation of the site induced by the applied current, and the control unit is adapted to measure the level of stimulation of the site, using the at least one of the electrodes.

In an embodiment, the site includes the SPG, and the electrodes are adapted to be placed in the vicinity of the SPG.

For some applications, the control unit is adapted to measure the level of stimulation using at least one of the at least one of the electrodes that applies the current to the site. For some applications, the control unit is adapted to measure the level of stimulation using at least one of the electrodes positioned in a vicinity of the at least one of the electrodes that applies the current to the site. For some applications, the control unit is adapted to measure, using the at least one of the electrodes, an electric field of nervous tissue, e.g., of the site, induced by the applied current.

There is also provided, in accordance with an embodiment of the present invention, apparatus including an implantable neural stimulator, which includes:

an elongated support element having a length of between 2.6 cm and 3 cm, having a distal end, and including, at the distal end, a surgical punch adapted to facilitate insertion of the support element through mucosa of the subject into a greater palatine canal of a subject, via a greater palatine foramen of the subject; and one or more electrodes fixed to the support element in a vicinity of the distal end thereof, and adapted to apply an electrical current to a sphenopalatine ganglion (SPG) of the subject.

For some applications, the support element includes a lock, adapted to hold the support element in place after insertion thereof into the greater palatine canal.

There is further provided, in accordance with an embodiment of the present invention, apparatus including an implantable neural stimulator, which includes:

an elongated support element having a length of between 2.6 cm and 3 cm, having a distal end, and adapted to be placed in a greater palatine canal of a subject; one or more electrodes fixed to the support element in a vicinity of the distal end thereof, and adapted to apply an electrical current to a sphenopalatine ganglion (SPG) of the subject; and a needle shaped so as to define a sharp distal end and a bore, which bore is adapted to hold the support element and the electrodes during insertion of the support element and the electrodes into the greater palatine canal, and to be withdrawn from the greater palatine canal thereafter, leaving the support element and electrodes in the greater palatine canal.

For some applications, the support element includes a lock, adapted to hold the support element in place after insertion thereof into the greater palatine canal.

There is still further provided, in accordance with an embodiment of the present invention, apparatus including an implantable neural stimulator, which includes:

one or more electrodes adapted to apply an electrical current to tissue of a subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; a receiver, electrically coupled to the one or more electrodes; an oral appliance, which includes: a capsule, which is configured to be placed and held between an alveolar process and an inner surface of a cheek of the subject; a wireless transmitter, adapted to be wirelessly coupled to the receiver; and an elongated coupling element, which couples the transmitter to the capsule; and a power source, electrically coupled to the wireless transmitter.

In an embodiment, the capsule includes the power source. Alternatively, the apparatus includes a cable, and the power source is adapted to be placed outside of a body of the subject, and is physically and electrically coupled to the capsule via the cable.

For some applications, the capsule is generally cylindrical. For some applications, the capsule includes a soft coating.

In an embodiment, the coupling element is configured such that the transmitter is positioned on a lingual side of teeth of the subject when the capsule is held between the alveolar process and the inner surface of the cheek. For some applications, the coupling element is configured to pass over an occlusal surface of one or more teeth of the subject. Alternatively, the coupling element is configured to pass around a distal surface of a most distal molar of the subject.

There is additionally provided, in accordance with an embodiment of the present invention, a method including:

inserting an elongated support element into a body of a subject, the element having a length of between about 1.8 cm and about 4 cm, and having proximal and distal ends; wirelessly transmitting energy from within an oral cavity of the subject; receiving the energy at the support element; and using the received energy, applying, from a vicinity of the distal end of the support element, an electrical current to a sphenopalatine ganglion (SPG) of the subject.

In an embodiment, inserting the support element includes:

preparing a submucosal surface on a hard palate of the subject; inserting the support element into a greater palatine canal of the subject; and placing a circuit module, which is fixed to the proximal end of the support element, against the prepared submucosal surface, and receiving the energy at the support element includes receiving the energy at the circuit module.

In an embodiment, inserting the support element includes:

preparing a submucosal surface on an alveolar process of a maxilla of the subject; inserting the support element into a greater palatine canal of the subject; and placing a circuit module, which is fixed to the proximal end of the support element, against the prepared submucosal surface, and receiving the energy at the support element includes receiving the energy at the circuit module.

There is yet additionally provided, in accordance with an embodiment of the present invention, a method including:

wirelessly transmitting energy from within an oral cavity of a subject; receiving the energy; and using the received energy, applying an electrical current to tissue of the subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve.

There is also provided, in accordance with an embodiment of the present invention, a method including:

inserting an elongated support element into a greater palatine canal of the subject, such that the support element extends from a palate of the subject to a sphenopalatine ganglion (SPG) of the subject, the support element having a distal end; and applying, from a vicinity of the distal end, an electrical current to the SPG.

There is further provided, in accordance with an embodiment of the present invention, a method including applying an electrical current to a greater palatine nerve of a subject from a site in a vicinity of a greater palatine foramen of a subject.

There is still further provided, in accordance with an embodiment of the present invention, a method including:

implanting, between oral mucosa and a palate of the subject, a submucosal antenna that includes at least one coil; wirelessly transmitting energy to the submucosal antenna; receiving the energy at the submucosal antenna; and using the energy, applying an electrical current to tissue of a subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve.

There is additionally provided, in accordance with an embodiment of the present invention, a method method including performing a calibration procedure by applying an electrical current to an anatomical site of a subject, during a plurality of calibration periods, from respective different sets of one or more stimulation sites in a vicinity of the anatomical site, the anatomical site selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve.

There is yet additionally provided, in accordance with an embodiment of the present invention, a method including:

placing a set of one or more electrodes in a vicinity of a site of a subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; driving at least one of the electrodes to apply an electrical current to the site; and using at least one of the electrodes, measuring a level of stimulation induced by the applied current.

There is also provided, in accordance with an embodiment of the present invention, a method including:

inserting, into a greater palatine canal of a subject, via a greater palatine foramen of the subject, an elongated support element having a length of between 2.6 cm and 3 cm and having a distal end, by using the distal end of the support element to punch an incision in mucosa of the subject; and applying, from a vicinity of the distal end of the support element, an electrical current to a sphenopalatine ganglion (SPG) of the subject.

There is further provided, in accordance with an embodiment of the present invention, a method including:

placing an elongated support element, having a length of between 2.6 cm and 3 cm and having a distal end, into a bore of a needle shaped so as to define a sharp distal end; inserting, into a greater palatine canal of a subject, the needle holding the support element; withdrawing the needle from the greater palatine canal thereafter, leaving the support element in the greater palatine canal; and applying, from a vicinity of the distal end of the support element, an electrical current to a sphenopalatine ganglion (SPG) of the subject.

There is still further provided, in accordance with an embodiment of the present invention, a method including:

placing a capsule between an alveolar process and an inner surface of a cheek of a subject; placing, in an oral cavity of the subject, a wireless transmitter coupled to the capsule by an elongated coupling element; wirelessly transmitting energy from the wireless transmitter; and receiving the energy, and, using the received energy, applying an electrical current to tissue of the subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve.

There is additionally provided, in accordance with an embodiment of the present invention, apparatus including:

an instrument, adapted to detect an indication of cerebral blood flow (CBF) of a subject, and to generate a signal responsive thereto; one or more electrodes, adapted to be placed in a vicinity of a site of the subject selected from a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; and a control unit, adapted to: receive the signal, drive the one or more electrodes to apply a current to the site capable of inducing a change in the CBF, and configure a parameter of the current responsively to the signal.

For some applications, the instrument includes a laser Doppler perfusion device, a transcranial Doppler ultrasonography device, a thermometer, or a near infrared spectroscopy (NIRS) device. Alternatively, the instrument includes an image sensor, adapted to image an eye of the subject, and the indication of CBF includes an indication of vasodilation of blood vessels of the eye. For some applications, the indication of vasodilation of the blood vessels of the eye includes a ratio of red to white in a sclera of the eye, and the instrument is adapted to determine the ratio.

There is yet additionally provided, in accordance with an embodiment of the present invention, a method including:

placing one or more electrodes in a vicinity of a site of a subject selected from a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; applying a current to the site capable of inducing a change in cerebral blood flow (CBF) of the subject; detecting an indication of the CBF; and responsively to the indication, adjusting at least one of: a placement of the electrodes, and a parameter of the applied current.

There is further provided, in accordance with an embodiment of the present invention, apparatus for treatment, including:

one or more electrodes, configured to be applied to a site of a subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; and adverse cerebrovascular condition treatment functionality, which includes a control unit configured to: drive the one or more electrodes to apply electrical stimulation to the site during a plurality of stimulation periods which includes at least first and last stimulation periods, set an inter-period interval between initiation of the first stimulation period and initiation of the last stimulation period to be at least 24 hours, and configure the stimulation during the first and last stimulation periods to induce at least one neuroprotective occurrence selected from the group consisting of: an increase in cerebral blood flow (CBF) of the subject, and a release of one or more neuroprotective substances.

For some applications, the control unit is configured to set the inter-period interval to be no more than a maximum value. For some applications, the control unit is configured to set the inter-period interval to be no more than nine months.

In an embodiment, the control unit is configured to store a maximum total time of stimulation per each time period having a given duration, and to drive the one or more electrodes to apply the stimulation no more than the maximum total time per each time period having the given duration.

In an embodiment, the plurality of stimulation periods includes at least one second stimulation period between the first and last stimulation periods, and the control unit is configured to drive the one or more electrodes to apply the stimulation during the first, second, and last stimulation periods, and to configure the stimulation during the first, second, and last stimulation periods to induce the at least one neuroprotective occurrence.

In an embodiment, the initiation of the last stimulation period occurs simultaneously with a conclusion of the first stimulation period, and the control unit is configured to drive the one or more electrodes to apply the stimulation continuously from the initiation of the first stimulation period to a conclusion of the last stimulation period. Alternatively, the initiation of the last stimulation period occurs after a conclusion of the first stimulation period, and the control unit is configured to withhold driving the one or more electrodes to apply the stimulation during at least one non-stimulation period between the conclusion of the first stimulation period and the initiation of the last stimulation period.

For some applications, the control unit is configured to drive the one or more electrodes to apply the stimulation for between one and six hours during each of the first and last stimulation periods.

For some applications, the control unit is configured to set a strength of the stimulation during at least one of the plurality of stimulation periods to be insufficient to induce a significant increase in permeability of a blood-brain barrier (BBB) of the subject. For example, the control unit may be configured to set the strength of the stimulation during the at least one of the plurality of stimulation periods to be less than 40% of a strength that is sufficient to induce the significant increase in permeability of the BBB.

In an embodiment, the apparatus includes a user interface, which is configured to receive as input a treatment duration value, and the control unit is configured to set the inter-period interval to be equal to the inputted treatment duration value. For some applications, the control unit is configured to store a predetermined maximum treatment duration value, and to compare the inputted treatment duration value with the maximum treatment duration value.

For some applications, the control unit is configured to set the inter-period interval to be at least 48 hours. For some applications, the control unit is configured to drive the one or more electrodes to apply the stimulation non-continuously during two or more of the plurality of the stimulation periods during each 24-hour period between the initiation of the first stimulation period and the initiation of the last stimulation period.

In an embodiment, the control unit is configured to set the inter-period interval to be at least one week. For some applications, the plurality of stimulation periods includes a plurality of daily stimulation periods, and the control unit is configured to drive the one or more electrodes to apply the stimulation during at least one of the daily stimulation periods on every day between the initiation of the first stimulation period and the initiation of the last stimulation period, and to configure the stimulation during the plurality of daily stimulation periods to induce the at least one neuroprotective occurrence.

For some applications, the control unit is configured to drive the one or more electrodes to apply the stimulation for at least 30 minutes every day, such as at least 60 minutes every day, between the initiation of the first stimulation period and the initiation of the last stimulation period. For some applications, the control unit is configured to set the inter-period interval to be at least two weeks, such as at least four weeks.

For some applications, the control unit is configured to set a strength of the stimulation during at least one of the plurality of stimulation periods to be less than 40% of a strength that induces a maximum increase in CBF in the subject that is achievable by applying the stimulation. Alternatively or additionally, for some applications, the control unit is configured to set a strength of the stimulation during at least one of the plurality of stimulation periods to a level that induces less than 40% of a maximum increase in CBF in the subject that is achievable by applying the stimulation.

For some applications, the control unit is configured to drive the one or more electrodes to apply the stimulation for less than six hours during each of the first and last stimulation periods.

In an embodiment, the site includes the SPG, and the one or more electrodes are configured to be applied to the SPG. For some applications, the apparatus includes an elongated support element configured to be placed within a greater palatine canal of the subject, sized to extend from a palate of the subject to the SPG, and having a distal end, and the electrodes are fixed to the support element in a vicinity of the distal end thereof.

In an embodiment, the control unit is configured to drive the one or more electrodes to apply the stimulation during the first period at a first stimulation strength and during the last period at a second stimulation strength, and to set the second stimulation strength to be different from the first stimulation strength, such as less than or greater than the first stimulation strength.

For some applications, the adverse cerebrovascular condition treatment functionality includes stroke treatment functionality, such as ischemic stroke treatment functionality.

There is further provided, in accordance with an embodiment of the present invention, a method for treatment, including:

identifying that a subject suffers from an adverse cerebrovascular condition; responsively to the identifying, applying electrical stimulation to a site of the subject during a plurality of stimulation periods which includes at least first and last stimulation periods, the site selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; setting an inter-period interval between initiation of the first stimulation period and initiation of the last stimulation period to be at least 24 hours; and configuring the stimulation during the first and last stimulation periods to induce at least one neuroprotective occurrence selected from the group consisting of: an increase in cerebral blood flow (CBF) of the subject, and a release of one or more neuroprotective substances.

In an embodiment, the adverse cerebrovascular condition includes an ischemic stroke, and identifying that the subject suffers from the condition includes identifying that the subject has experienced the ischemic stroke. Alternatively, for some applications, the condition includes an aneurysm or an arteriovenous malformation, or an anoxic brain injury caused, for example, by near drowning, kidney failure, heart failure, chemical exposure, myocardial infarction, or electric shock.

For some applications, applying the stimulation during the first and last stimulation periods includes applying the stimulation for less than six hours during each of the first and last stimulation periods.

In an embodiment, applying the stimulation includes placing an electrical stimulator in a vicinity of the site, and activating the stimulator to apply the stimulation.

In an embodiment, the condition includes an adverse cerebrovascular event, identifying that the subject suffers from the condition includes identifying that the subject has experienced the event, and applying the stimulation includes applying the stimulation beginning at least three hours after the event, such as at least six hours after the event, at least nine hours after the event, at least 12 hours after the event, or at least 24 hours after the event.

There is still further provided, in accordance with an embodiment of the present invention, apparatus for treating a subject, including:

one or more electrodes, configured to be applied to a site of the subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; and a control unit, configured to: drive the one or more electrodes to apply electrical stimulation to the site, and configure the stimulation to excite nervous tissue of the site at a strength sufficient to induce at least one neuroprotective occurrence selected from the group consisting of: an increase in cerebral blood flow (CBF) of the subject, and a release of one or more neuroprotective substances, and insufficient to induce a significant increase in permeability of a blood-brain barrier (BBB) of the subject.

In an embodiment, the control unit is configured to set the strength to less than 90% of a strength sufficient to induce the significant increase in the permeability of the BBB. Alternatively or additionally, the control unit is configured to set the strength to less than 40% of a strength sufficient to induce the significant increase in the permeability of the BBB.

For some applications, the control unit is configured to set the strength to more than 50% of a strength sufficient to induce the significant increase in the permeability of the BBB.

In an embodiment, the site includes the SPG, and the electrodes are configured to be applied to the SPG. For some applications, the apparatus includes an elongated support element configured to be placed within a greater palatine canal of the subject, sized to extend from a palate of the subject to the SPG, and having a distal end, and the electrodes are fixed to the support element in a vicinity of the distal end thereof.

There is additionally provided, in accordance with an embodiment of the present invention, apparatus for treating a subject, including:

one or more electrodes, configured to be applied to a site of the subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; and a control unit, configured to: drive the one or more electrodes to apply electrical stimulation to the site during at least a first period of time and a second period of time after the first period, each of the first and second periods of time having a duration of at least one minute, and configure the stimulation to excite nervous tissue of the site during the first period at a first stimulation strength and during the second period at a second stimulation strength less than the first stimulation strength, wherein the first and second stimulation strengths are sufficient to induce an increase in cerebral blood flow (CBF) of the subject.

In an embodiment, each of the first and second periods has a duration of at least one hour, and the control unit is configured to drive the one or more electrodes to apply the stimulation during the first and second periods each having the duration of at least one hour.

In an embodiment, the control unit is configured to set the first and second stimulation strengths to be insufficient to induce a significant increase in permeability of a blood-brain barrier (BBB) of the subject.

For some applications, the control unit is configured to receive an input of a point in time, and to determine the first and second time periods with respect to the point in time.

In an embodiment, the control unit is configured to apply the stimulation during a third period of time after the second period, and configure the stimulation to excite the nervous tissue during the third period at a third stimulation strength that is less than the second stimulation strength.

In an embodiment, the site includes the SPG, and the electrodes are configured to be applied to the SPG. For some applications, the apparatus includes an elongated support element configured to be placed within a greater palatine canal of the subject, sized to extend from a palate of the subject to the SPG, and having a distal end, and the electrodes are fixed to the support element in a vicinity of the distal end thereof.

There is still additionally provided, in accordance with an embodiment of the present invention, a method for treating a subject, including:

applying electrical stimulation to a site of the subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; and configuring the stimulation to excite nervous tissue of the site at a strength sufficient to induce at least one neuroprotective occurrence selected from the group consisting of: an increase in cerebral blood flow (CBF) of the subject, and a release of one or more neuroprotective substances, and insufficient to induce a significant increase in permeability of a blood-brain barrier (BBB) of the subject.

There is yet additionally provided, in accordance with an embodiment of the present invention, a method for treating a subject, including:

applying electrical stimulation to a site of the subject during at least a first period of time and a second period of time after the first period, each of the first and second periods of time having a duration of at least one minute, the site selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; and configuring the stimulation to excite nervous tissue of the site during the first period at a first stimulation strength and during the second period at a second stimulation strength less than the first stimulation strength, wherein the first and second stimulation strengths are sufficient to induce an increase in cerebral blood flow (CBF) of the subject.

There is also provided, in accordance with an embodiment of the present invention, a method for treatment, including:

identifying that a subject has suffered from an adverse cerebrovascular event; responsively to the identifying, applying, beginning at least three hours after the event, electrical stimulation to a site of the subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; and configuring the stimulation to excite nervous tissue of the site at a strength sufficient to induce at least one neuroprotective occurrence selected from the group consisting of: an increase in cerebral blood flow (CBF) of the subject, and a release of one or more neuroprotective substances.

For some applications, applying the stimulation includes applying the stimulation beginning at least six hours after the event, such as least nine hours after the event, at least 12 hours after the event, or at least 24 hours after the event.

For some applications, configuring the stimulation includes setting the strength to be insufficient to induce a substantial increase in permeability of a blood-brain barrier (BBB) of the subject.

In an embodiment, the event includes a stroke, e.g., an ischemic stroke, and applying the stimulation includes applying the stimulation beginning at least three hours after the stroke. Alternatively, for some applications, the event includes an aneurysm or an arteriovenous malformation, or an anoxic brain injury caused, for example, by near drowning, kidney failure, heart failure, chemical exposure, myocardial infarction, or electric shock.

For some applications, applying the stimulation includes applying the stimulation intermittently.

In an embodiment, applying the stimulation includes applying the stimulation during a plurality of stimulation periods which includes at least first and last stimulation periods, wherein initiation of the first period is at least three hours after the event; and setting an inter-period interval between the initiation of the first stimulation period and initiation of the last stimulation period to be at least 24 hours, and configuring the stimulation includes configuring the stimulation during the first and last stimulation periods to induce the at least one neuroprotective occurrence.

In an embodiment, the site includes the SPG, and applying the stimulation includes applying the stimulation to the SPG. For some applications, applying the stimulation includes placing an elongated support element within a greater palatine canal of the subject, sized to extend from a palate of the subject to the SPG, and having a distal end; and applying the stimulation from a vicinity of the distal end of the support element.

There is further provided, in accordance with an embodiment of the present invention, a method for treating a subject, including:

applying, for at least 15 minutes per day during a period of at least one week, an electrical current to a site of the subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; and configuring the current to excite nervous tissue of the site at a strength sufficient to induce at least one of: an increase in cerebral blood flow (CBF) of the subject, and a release of one or more neuroprotective substances.

For some applications, configuring the current includes setting the strength to be less than 40% of a strength that induces a maximum increase in CBF in the subject that is achievable by applying the current. Alternatively or additionally, configuring the current includes setting the strength to a level that induces less than 40% of a maximum increase in CBF in the subject that is achievable by applying the current.

For some applications, applying the current includes applying the current for less than 6 hours per day.

For some applications, applying the current includes implanting an electrical stimulator in a vicinity of the site, and activating the stimulator to apply the current.

In an embodiment, configuring the current includes setting the strength to be insufficient to induce a significant increase in permeability of a blood-brain barrier (BBB) of the subject. For some applications, setting the strength includes setting the strength to be less than 40% of a strength that is sufficient to induce the significant increase in permeability of the BBB.

In an embodiment, the site includes the SPG, and applying the current includes applying the current to the SPG. For some applications, applying the current includes: placing an elongated support element within a greater palatine canal of the subject, sized to extend from a palate of the subject to the SPG, and having a distal end; and applying the current from a vicinity of the distal end of the support element.

For some applications, applying the current includes applying the current for at least 30 minutes per day during the period of at least one week, such as for at least 60 minutes per day during the period of at least one week.

There is additionally provided, in accordance with an embodiment of the present invention, a method for treating a brain tumor of a subject, including:

administering a chemotherapeutic drug to the subject; during a first period of time during which the drug is at a first level in a systemic circulation of the subject, applying electrical stimulation to a site of the subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve, and configuring the stimulation to excite nervous tissue of the site at a first strength sufficient to induce an increase in permeability of a blood-tumor barrier (BTB) of the subject; and during a second period of time during which the drug is at a second level in the systemic circulation, the second level lower than the first level, applying the stimulation to the site, and configuring the stimulation to excite the nervous tissue at a second strength that is greater than the first strength.

In an embodiment, configuring the stimulation during the first period includes setting the first strength to be insufficient to induce a significant increase in permeability of a blood-brain barrier (BBB) of the subject. Alternatively or additionally, configuring the stimulation during the second period includes setting the second strength to be sufficient to induce a significant increase in permeability of a BBB of the subject. Further alternatively or additionally, configuring the stimulation during the first and second periods includes setting the first strength to be insufficient to induce a significant increase in permeability of a BBB of the subject, and the second strength to be sufficient to induce the significant increase in the permeability of the BBB.

In an embodiment, the site includes the SPG, and applying the stimulation includes applying the stimulation to the SPG. For some applications, applying the stimulation during the first and second periods includes: placing an elongated support element within a greater palatine canal of the subject, sized to extend from a palate of the subject to the SPG, and having a distal end; and applying the stimulation from a vicinity of the distal end of the support element.

There is yet additionally provided, in accordance with an embodiment of the present invention, a method for treating a brain tumor of a subject, including:

administering a chemotherapeutic drug to the subject; applying electrical stimulation to a site of the subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; and configuring the stimulation to excite nervous tissue of the site at a strength sufficient to induce an increase in permeability of a blood-tumor barrier (BTB) of the subject, but insufficient to induce a substantial increase in permeability of a blood-brain barrier (BBB) of the subject.

In an embodiment, the site includes the SPG, and applying the stimulation includes applying the stimulation to the SPG. For some applications, applying the stimulation includes: placing an elongated support element within a greater palatine canal of the subject, sized to extend from a palate of the subject to the SPG, and having a distal end; and applying the stimulation from a vicinity of the distal end of the support element.

There is also provided, in accordance with an embodiment of the present invention, apparatus for treating a condition of a subject, including:

a coil, adapted to be positioned in a vicinity of a site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, an infraorbital nerve of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and a control unit, adapted to drive the coil to generate a magnetic field in the vicinity of the site capable of inducing an increase in cerebral blood flow (CBF) of the subject.

In an embodiment, the site includes the SPG of the subject, and the coil is adapted to be positioned in the vicinity of the SPG.

For some applications, the control unit is adapted to generate the magnetic field with a strength sufficient to stimulate the site, and insufficient to substantially stimulate brain tissue of the subject.

For some applications, the apparatus includes a cooling element, adapted to prevent excessive heating of the coil.

For some applications, the coil includes between about 4 and about 30 loops of wire.

In an embodiment, the coil is adapted to be inserted into a nasal cavity of the subject.

For some applications, the coil is substantially figure-eight-shaped. Alternatively, the coil is substantially 4-leaf-shaped. Further alternatively, the coil is substantially circular.

For some applications, the coil has a diameter of between about 3 mm and about 12 mm.

In an embodiment, the coil is adapted to be placed in a vicinity of a temporomandibular joint of the subject. For some applications, the coil has a diameter of between about 3 cm and about 12 cm.

In an embodiment, the coil is adapted to be placed around at least a portion of a head of the subject. For some applications, the coil has a diameter of between about 3 cm and about 12 cm.

There is additionally provided, in accordance with an embodiment of the present invention, apparatus for treating a condition of a subject, including:

a coil, adapted to be positioned in a vicinity of a site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, an infraorbital nerve of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and a control unit, adapted to drive the coil to generate a magnetic field in the vicinity of the site capable of inducing an increase in permeability of a blood-brain barrier (BBB) of the subject.

In an embodiment, the site includes the SPG of the subject, and the coil is adapted to be positioned in the vicinity of the SPG.

For some applications, the control unit is adapted to generate the magnetic field with a strength sufficient to stimulate the site, and insufficient to substantially stimulate brain tissue of the subject.

For some applications, the apparatus includes a cooling element, adapted to prevent excessive heating of the coil.

For some applications, the coil includes between about 4 and about 30 loops of wire.

In an embodiment, the coil is adapted to be inserted into a nasal cavity of the subject.

For some applications, the coil is substantially figure-eight-shaped. Alternatively, the coil is substantially 4-leaf-shaped. Further alternatively, the coil is substantially circular. For some applications, the coil has a diameter of between about 3 mm and about 12 mm.

In an embodiment, the coil is adapted to be placed in a vicinity of a temporomandibular joint of the subject. For some applications, the coil has a diameter of between about 30 mm and about 120 mm.

In an embodiment, the coil is adapted to be placed around at least a portion of a head of the subject. For some applications, the coil has a diameter of between about 10 cm and about 25 cm.

There is also provided, in accordance with an embodiment of the present invention, apparatus for facilitating a diagnosis of a condition of a subject, including:

a coil, adapted to be positioned in a vicinity of a site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, an infraorbital nerve of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and a control unit, adapted to drive the coil to generate a magnetic field in the vicinity of the site capable of inducing an increase in permeability of a blood-brain barrier (BBB) of the subject sufficient to increase passage of a diagnostic agent across the BBB into a central nervous system (CNS) of the subject.

In an embodiment, the site includes the SPG of the subject, and the coil is adapted to be positioned in the vicinity of the SPG.

For some applications, the control unit is adapted to generate the magnetic field with a strength sufficient to stimulate the site, and insufficient to substantially stimulate brain tissue of the subject.

For some applications, the apparatus includes a cooling element, adapted to prevent excessive heating of the coil.

For some applications, the coil includes between about 4 and about 30 loops of wire.

In an embodiment, the coil is adapted to be inserted into a nasal cavity of the subject. For some applications, the coil is substantially figure-eight-shaped. Alternatively, the coil is substantially 4-leaf-shaped. Further alternatively, the coil is substantially circular. For some applications, the coil has a diameter of between about 3 mm and about 12 mm.

In an embodiment, the coil is adapted to be placed in a vicinity of a temporomandibular joint of the subject. For some applications, the coil has a diameter of between about 3 cm and about 12 cm.

In an embodiment, the coil is adapted to be placed around at least a portion of a head of the subject. For some applications, the coil has a diameter of between about 3 cm and about 12 cm.

There is further provided, in accordance with an embodiment of the present invention, apparatus for facilitating delivery of a drug to a subject, including:

a coil, adapted to be positioned in a vicinity of a site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, an infraorbital nerve of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and a control unit, adapted to drive the coil to generate a magnetic field in the vicinity of the site capable of inducing an increase in permeability of a blood-brain barrier (BBB) of the subject sufficient to increase passage of the drug across the BBB into a central nervous system (CNS) of the subject.

In an embodiment, the site includes the SPG of the subject, and the coil is adapted to be positioned in the vicinity of the SPG.

For some applications, the control unit is adapted to generate the magnetic field with a strength sufficient to stimulate the site, and insufficient to substantially stimulate brain tissue of the subject.

For some applications, the apparatus includes a cooling element, adapted to prevent excessive heating of the coil.

For some applications, the coil includes between about 4 and about 30 loops of wire.

In an embodiment, the coil is adapted to be inserted into a nasal cavity of the subject. For some applications, the coil is substantially figure-eight-shaped. Alternatively, the coil is substantially 4-leaf-shaped. Further alternatively, the coil is substantially circular. For some applications, the coil has a diameter of between about 3 mm and about 12 mm.

In an embodiment, the coil is adapted to be placed in a vicinity of a temporomandibular joint of the subject. For some applications, the coil has a diameter of between about 3 cm and about 12 cm.

In an embodiment, the coil is adapted to be placed around at least a portion of a head of the subject. For some applications, the coil has a diameter of between about 3 cm and about 12 cm.

There is still further provided, in accordance with an embodiment of the present invention, apparatus for facilitating a diagnosis of a condition of a subject, including:

a coil, adapted to be positioned in a vicinity of a site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, an infraorbital nerve of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and a control unit, adapted to drive the coil to generate a magnetic field in the vicinity of the site capable of inducing an increase in permeability of a blood-brain barrier (BBB) of the subject sufficient to increase passage of a constituent of a central nervous system (CNS) of the subject across the BBB into a systemic blood circulation of the subject.

In an embodiment, the site includes the SPG of the subject, and the coil is adapted to be positioned in the vicinity of the SPG.

For some applications, the control unit is adapted to generate the magnetic field with a strength sufficient to stimulate the site, and insufficient to substantially stimulate brain tissue of the subject.

For some applications, the apparatus includes a cooling element, adapted to prevent excessive heating of the coil.

For some applications, the coil includes between about 4 and about 30 loops of wire.

In an embodiment, the coil is adapted to be inserted into a nasal cavity of the subject. For some applications, the coil is substantially figure-eight-shaped. Alternatively, the coil is substantially 4-leaf-shaped. Alternatively, the coil is substantially circular. For some applications, the coil has a diameter of between about 3 mm and about 12 mm.

In an embodiment, the coil is adapted to be placed in a vicinity of a temporomandibular joint of the subject. For some applications, the coil has a diameter of between about 3 cm and about 12 cm.

In an embodiment, the coil is adapted to be placed around at least a portion of a head of the subject. For some applications, the coil has a diameter of between about 3 cm and about 12 cm.

There is also provided, in accordance with an embodiment of the present invention, a method for treating a condition of a subject, including:

selecting a site from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, an infraorbital nerve of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and generating a magnetic field in the vicinity of the site capable of inducing an increase in cerebral flood flow of the subject, so as to treat the condition.

There is further provided, in accordance with an embodiment of the present invention, a method for treating a condition of a subject, including:

selecting a site from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, an infraorbital nerve of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and generating a magnetic field in the vicinity of the site capable of inducing an increase in permeability of a blood-brain barrier (BBB) of the subject, so as to treat the condition.

There is also provided, in accordance with an embodiment of the present invention, a method for facilitating a diagnosis of a condition of a subject, including:

selecting a site from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, an infraorbital nerve of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and generating a magnetic field in the vicinity of the site capable of inducing an increase in permeability of a blood-brain barrier (BBB) of the subject sufficient to increase passage of a diagnostic agent across the BBB into a central nervous system (CNS) of the subject.

There is further provided, in accordance with an embodiment of the present invention, a method for facilitating delivery of a drug to a subject, including:

selecting a site from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, an infraorbital nerve of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and generating a magnetic field in the vicinity of the site capable of inducing an increase in permeability of a blood-brain barrier (BBB) of the subject sufficient to increase passage of the drug across the BBB into a central nervous system (CNS) of the subject.

In an embodiment, the method includes administering the drug to a body of the subject, in conjunction with generating the magnetic field.

There is still further provided, in accordance with an embodiment of the present invention, a method for facilitating a diagnosis of a condition of a subject, including:

selecting a site from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, an infraorbital nerve of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and generating a magnetic field in the vicinity of the site capable of inducing an increase in permeability of a blood-brain barrier (BBB) of the subject sufficient to increase passage of a constituent of a central nervous system (CNS) of the subject across the BBB into a systemic blood circulation of the subject.

For some applications, the method includes measuring a concentration of the constituent in the systemic blood circulation.

There is also provided, in accordance with an embodiment of the present invention, a method for modifying a property of a brain of a subject, including generating a magnetic field in the vicinity of a branch of a cranial nerve V of the subject configured to affect physiological activity of a sphenopalatine ganglion (SPG) of the subject at a level sufficient to induce an increase in permeability of a blood-brain barrier (BBB) of the subject.

There is further provided, in accordance with an embodiment of the present invention, a method for modifying a property of a brain of a subject, including generating a magnetic field in the vicinity of a branch of a cranial nerve V of the subject configured to affect physiological activity of a sphenopalatine ganglion (SPG) of the subject at a level sufficient to induce an increase in cerebral blood flow (CBF) of the subject.

The present invention will be more fully understood from the following detailed description of the embodiments thereof, taken together with the drawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of a neural stimulation system, in accordance with an embodiment of the present invention;

FIG. 2 is a schematic cross-sectional illustration of a spring-loaded locking element engaging the greater palatine canal, in accordance with an embodiment of the present invention;

FIGS. 3A and 3B are schematic illustrations of a laterally displaced configuration of a stimulator of the system of FIG. 1, in accordance with an embodiment of the present invention;

FIGS. 4A and 4B are schematic illustrations of out-of-plane configurations of the stimulator of the system of FIG. 1, in accordance with respective embodiments of the present invention;

FIGS. 5A-D are schematic illustrations of a longitudinally-oriented configuration of the stimulator of the system of FIG. 1, in accordance with an embodiment of the present invention;

FIGS. 6A-D are schematic illustrations of variable-length support elements of the system of FIG. 1, in accordance with respective embodiments of the present invention;

FIGS. 7A-B are schematic illustrations of an oral element of the system of FIG. 1, in accordance with respective embodiments of the present invention;

FIG. 8 is a schematic illustration of an oral element of the system of FIG. 1 coupled to an oral appliance, in accordance with an embodiment of the present invention;

FIG. 9 is a schematic illustration of a contact-based energy transmission configuration of the system of FIG. 1, in accordance with an embodiment of the present invention;

FIG. 10 is a schematic illustration of a configuration of a contact of the configuration of FIG. 9, in accordance with an embodiment of the present invention;

FIG. 11A-B are schematic illustrations of energy and data transmission paths between components of the system of FIG. 1, in accordance with respective embodiments of the present invention;

FIG. 12 is a schematic illustration of another neural stimulation system, in accordance with an embodiment of the present invention;

FIG. 13 is a schematic illustration of an implantable submucosal antenna of the system of FIG. 12, in accordance with an embodiment of the present invention;

FIGS. 14A-B are schematic illustrations of energy and data transmission paths between components of the system of FIG. 12, in accordance with respective embodiments of the present invention;

FIG. 15 is a schematic illustration of a configuration of the stimulator of the stimulation system of FIGS. 12-14, in accordance with an embodiment of the present invention;

FIG. 16 is a schematic illustration of an electrode configuration, in accordance with an embodiment of the present invention;

FIGS. 17A-C are schematic illustrations of an array of electrodes, in accordance with an embodiment of the present invention;

FIG. 18 is a schematic pictorial view of a stimulation system for stimulation of a modulation target site, in accordance with an embodiment of the present invention;

FIG. 19 is a schematic illustration of a vasodilation measurement instrument, in accordance with an embodiment of the present invention;

FIG. 20 is a schematic illustration of a laser Doppler imaging (LDI) device, in accordance with an embodiment of the present invention;

FIG. 21 is a schematic illustration of a thermometer, in accordance with an embodiment of the present invention;

FIG. 22 is a schematic illustration of a transcranial Doppler ultrasonography device, in accordance with an embodiment of the present invention;

FIGS. 23A and 23B are schematic illustrations of nasal magnetic induction devices, in accordance with an embodiment of the present invention;

FIGS. 24A and 24B are schematic illustrations of an external magnetic induction device, in accordance with an embodiment of the present invention;

FIG. 25 is a schematic pictorial view of an electrical stimulation system comprising an implantable stimulator for stimulation of an MTS, in accordance with an embodiment of the present invention;

FIG. 26 is a schematic pictorial view of another stimulator for stimulation of an MTS, in accordance with an embodiment of the present invention;

FIG. 27 is a graph illustrating electrical stimulation protocols, in accordance with an embodiment of the present invention;

FIG. 28 is a graph showing a rehabilitation protocol for treating stroke, in accordance with an embodiment of the present invention;

FIG. 29 is a graph showing changes in cerebral blood flow (CBF) vs. baseline using three different SPG stimulation protocols, measured in accordance with an embodiment of the present invention;

FIG. 30 is a graph showing the effect of SPG stimulation beginning three hours after permanent middle cerebral artery occlusion (pCMAO) in rats, measured in accordance with an embodiment of the present invention;

FIGS. 31 and 32 are graphs showing results of an in vivo experiment assessing the effect of SPG stimulation performed three hours following stroke, measured in accordance with an embodiment of the present invention;

FIGS. 33A-C are graphs showing the results of in vivo experiments assessing the effect of SPG stimulation performed three hours following stroke, measured in accordance with respective embodiments of the present invention;

FIG. 34 is a graph showing results of an in vivo experiment assessing the effect of rehabilitative SPG stimulation, measured in accordance with an embodiment of the present invention;

FIGS. 35A-C are graphs showing results of an in vivo experiment assessing the effect of rehabilitative SPG stimulation, measured in accordance with an embodiment of the present invention;

FIGS. 36A-H are graphs showing results of an in vivo experiment assessing the effect of long-term rehabilitative SPG stimulation, measured in accordance with an embodiment of the present invention; and

FIG. 37 is a graph showing a protocol for treating a brain tumor, in accordance with an embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 is a schematic illustration of a neural stimulation system 20, in accordance with an embodiment of the present invention. System 20 typically comprises an implantable neural stimulator 30, an oral element 32, and an external control unit 34. Stimulator 30 comprises an elongated support element 36, one or more electrodes 38 fixed to the support element in a vicinity of a distal end thereof, and circuitry 40 coupled to the support element in a vicinity of a proximal end thereof. Circuitry 40 typically comprises a wireless coupling element (which typically comprises a coil), and additional elements, such as one or more rectifiers, capacitors, amplifiers, or filters. One or more leads (not shown in FIG. 1), which pass along, through, or around support element 36, couple electrodes 38 to circuitry 40. Alternatively, the leads function as the support element, i.e., the support element does not comprise any structural elements in addition to the leads. Further alternatively, the leads provide a substantial portion of the structural support of the support element, and the balance of the structural support is provided by other elements. For example, support element 36 may comprise the leads and a flexible sleeve surrounding the leads; the leads supply most of the structural support of the support element, while the sleeve allows smooth passage of the leads through the greater palatine canal. Circuitry 40 is shown schematically in FIG. 1; several more detailed configurations of the circuitry are described hereinbelow with reference to FIGS. 3A-B, 4A-B, and 5A-D.

Stimulator 30 is adapted to be passed through a greater palatine foramen 42 of a hard palate 50 of an oral cavity 52 of a subject into a greater palatine canal 54, such that electrodes 38 are brought into a vicinity of a sphenopalatine ganglion (SPG) 56. For some applications, the entire stimulator is contained within greater palatine canal 54, while for other applications, at least a portion of the circuitry and/or the support element are positioned submucosally in the oral cavity. For clarity of illustration, the greater and lesser palatine nerves, and the greater and less palatine arteries are not shown in the figures. During an implantation procedure, stimulator 30 is typically passed through greater palatine foramen 42 posterior to the greater palatine nerve and artery, which are manipulated into an anterior position within the canal.

For some applications, electrodes 38 apply a monophasic waveform to SPG 56, while for other applications, electrodes 38 apply a biphasic waveform. Alternatively or additionally, waveforms and/or stimulation techniques may be used that are described in one or more of the patent applications incorporated by reference hereinbelow, or waveforms and/or stimulation techniques may be used that are known in the art of neural stimulation.

For some applications, the distal end of support element 36 comprises a surgical punch 60, which is adapted to be passed through mucosa 58 and greater palatine foramen 42 without requiring a prior surgical incision in the mucosa, i.e., without requiring the use of a surgical knife or other tool. Circuitry 40 is sufficiently small so as to be able to pass through the punch incision without requiring the incision to be surgically enlarged.

For some applications, stimulator 30 comprises a locking element, such as in a vicinity of the proximal end thereof, which is adapted to hold the stimulator in place after insertion. For some applications, the locking element comprises a screw, which is adapted to couple the stimulator to the palate or the alveolar process of the maxilla. Alternatively or additionally, the locking element comprises a bonding agent, which is adapted to bond the stimulator to the palate, the alveolar process of the maxilla, or an internal surface of greater palatine canal 54.

Reference is made to FIG. 2, which is a schematic cross-sectional illustration of a spring-loaded locking element 62 engaging greater palatine canal 54, in accordance with an embodiment of the present invention. Locking element 62 applies lateral pressure on the interior surface of a portion of greater palatine canal 54 in a vicinity of foramen 42, thereby locking elongated support element 36 in place in the canal. Locking element 62 is configured so as to not interfere with a descending palatine artery 64 or a greater palatine nerve 66, both of which pass through greater palatine canal 54.

For some applications, support element 36 has a length of between about 1.8 and about 3 cm, such as between about 2.6 cm and about 3 cm, e.g., between about 2.6 and about 3 cm, such as about 2.8 cm, and has a curvature that follows that of the greater palatine canal. For some applications, support element 36 has a diameter at its widest portion of between about 1 and about 4 mm. For some applications, support element 36 comprises a tube. For some applications, support element 36 is semi-rigid (i.e., it generally keeps its original shape during a placement procedure). For example, support element 36 may be sufficiently rigid to enable insertion of the support element into a body of the subject by pushing from a vicinity of a proximal end of the support element. For some applications, support element 36 and electrodes 38 together are similar to conventional concentric needle electrodes, such as Medtronic, Inc. needle electrode model DCN50, or Oxford Instruments Plc. needle electrode models X53153, X53155, X53156, X53158, or X53159.

Each of electrodes 38 typically comprises a suitable conductive material, for example, a physiologically-acceptable material such as silver, iridium, platinum, a platinum iridium alloy, titanium, nitinol, or a nickel-chrome alloy. For some applications, each of the electrodes has a surface area of between about 1 and about 8 mm², such as about 2.653 or about 6.123 mm². For some applications, electrodes 38 are recessed within support element 36, while for other applications the electrodes are flush with the surface of the support element, or protrude therefrom. Electrodes 38 are insulated from one another with a physiologically-acceptable material such as polyethylene, polyurethane, or a co-polymer of either of these. For some applications, the electrodes are spiral in shape, for better contact, and may have a hook shaped distal end for hooking into or near the SPG. Alternatively or additionally, the electrodes may comprise simple wire electrodes, spring-loaded “crocodile” electrodes, or adhesive probes, as appropriate. For some applications, the electrodes are coated with a biocompatible material configured to enhance the surface area of the electrodes, thereby increasing the capacitance and reducing the resistance of the electrodes. For example, the material may comprise a platinum/iridium alloy, and/or may be applied with a sputtering process, such as commercially available from Johnson Matthey Plc, Advanced Metals Technology division (London, UK).

Optionally, support element 36 comprises one or more marks (not shown) that indicate the depth of insertion of stimulator 30 into greater palatine canal 54. Alternatively or additionally, for some applications support element 36 comprises a stopper (not shown) in a vicinity of the marks, that mechanically prevents insertion of the support element into the canal beyond a certain depth.

Reference is made to FIGS. 3A-B, 4A-B, and 5A-D, which are schematic illustrations of several configurations of stimulator 30, in accordance with respective embodiments of the present invention. In these embodiments, stimulator 30 comprises a circuit module 41, which comprises circuitry 40 coupled to a printed circuit board. Circuit module 41 has a generally flat shape, typically with a thickness of less than about 2 mm, such as less than about 1.2 mm, e.g., about 1.05 mm. For some applications, one or more layers of coating are applied to circuit module 41, such as in order to provide a conforming, thin, smooth, watertight, biocompatible, and/or mechanically-protective surface. For example, a first, innermost coating may comprise an inert biocompatible polymer, such as Parylene C, having a thickness of between about 10 and about 15 microns. A second watertight mineral-based sealant, such as Al₂O₃, SiO₂, or Si₂N₃, may be applied over the innermost coating by sputtering. The thickness of the watertight sealant is typically between about 1 and about 2 microns. A third, outermost coating of an inert biocompatible polymer, such as Parylene C, having a thickness of between about 10 and about 15 microns, may be applied over the watertight sealant.

FIGS. 3A and 3B are schematic illustrations of a laterally displaced configuration of stimulator 30, in accordance with an embodiment of the present invention. FIG. 3A shows stimulator 30 in an unfolded position. Circuit module 41 has a generally flat shape, and may be generally elliptical, as shown in FIG. 3A, or may have another shape, such as rectangular. Prior to insertion in greater palatine canal 54, support element 36 is folded at a fold 44 at an angle α approximately equal to the angle between greater palatine canal 54 and hard palate 50 in a vicinity of foramen 42. During an implantation procedure, (a) a submucosal surface on the hard palate is prepared, such as by raising a mucosal flap, by creating a mucosal opening using a retractor, and/or by preparing a submucosal pocket using a tool which has generally the same shape and dimensions as circuit module 41, (b) support element 36 is inserted into greater palatine canal 54, (c) circuit module 41 is placed against the exposed lower surface of hard palate 50, and (d) mucosa 58 is closed over circuit module 41 and the portion of support element that protrudes from greater palatine canal 54. For implantation procedures during which a mucosal flap is raised, an approximately 3 cm incision is typically required to raise the mucosal flap. For some applications, the circuit module is coupled to the hard palate, such as by using at least one nail or screw (coupling not shown). Typically, the distal portion of support element 36 beyond fold 44 has a length L1 of between about 26 and about 30 mm, e.g., about 28 mm, and the entire stimulator 30 in an unfolded position, including circuit module 41, has a length L2 of between about 40 and about 44 mm, e.g., about 42 mm.

FIGS. 4A and 4B are schematic illustrations of out-of-plane configurations of stimulator 30, in accordance with respective embodiments of the present invention. In these configurations, a proximal end 46 of support element 36 is coupled directly to circuit module 41, such that an angle β between support element 36 and the surface of circuit module 41 is approximately equal to the angle between greater palatine canal 54 and hard palate 50 in a vicinity of foramen 42. As in the configuration shown in FIGS. 3A and 3B, circuit module 41 has a generally flat shape, and may be generally elliptical, or may have another shape, such as rectangular. In the configuration shown in FIG. 4A, proximal end 46 of support element 36 is coupled to circuit module 41 in a vicinity of a center of the surface of the circuit module. For some applications, the circuit module is coupled to the support element such that the longer axis or side of the circuit module is oriented in an anterior-posterior direction. Alternatively, the longer axis or side of the circuit module is oriented in a left-right direction, or in another direction. Typically, support element 36 has a length of between about 26 and about 30 mm, e.g., about 28 mm.

In the configuration shown in FIG. 4B, proximal end 46 is coupled to circuit module in a vicinity of an edge of the surface of the circuit module. The support element may be coupled to any point on the edge, e.g., in a vicinity of an end of a major axis or a minor axis of the circuit module. For some applications, proximal end 46 of support element 36 is coupled to circuit module 41 at a location between the center of the circuit module and the edge of the circuit module. For some applications, the circuit module is coupled to the support element such that the circuit module extends in an anterior direction, in a posterior direction, towards the center of the mouth, or towards the maxillary bone. For example, when the circuit module extends in a posterior direction or towards the center of the mouth, the circuit module is less likely to interfere with branches of the greater palatine nerve or greater palatine artery that extend in an anterior direction from greater palatine foramen 42. For some applications, circuit module 41 is generally kidney-shaped.

During an implantation procedure, (a) a submucosal surface on the hard palate is prepared, such as by raising a mucosal flap, by creating a mucosal opening using a retractor, and/or by preparing a submucosal pocket using a tool which has generally the same shape and dimensions as circuit module 41, (b) support element 36 is inserted into greater palatine canal 54, (c) circuit module 41 is placed against the exposed lower surface of hard palate 50, and (d) mucosa 58 is closed over circuit module 41. For implantation procedures during which a mucosal flap is raised, an approximately 7 mm incision is typically required to raise the mucosal flap. For some applications, the circuit module is coupled to the hard palate, such as by using at least one nail or screw (coupling not shown).

FIGS. 5A-D are schematic illustrations of a longitudinally-oriented configuration of stimulator 30, in accordance with an embodiment of the present invention. In this configuration, a proximal end 46 of support element 36 is coupled to circuit module 41. Circuit module 41 has a generally flat shape, and may be generally elliptical, as shown in FIG. 5A, or may have another shape, such as rectangular. As shown in FIGS. 5B-D, a proximal portion 48 of support element 36 which protrudes from greater palatine canal 54 is sufficiently flexible to follow the contour of the palate and alveolar process.

During an implantation procedure, (a) a submucosal surface on the hard palate is prepared, such as by raising a mucosal flap, by creating a mucosal opening using a retractor, and/or by preparing a submucosal pocket using a tool which has generally the same shape and dimensions as circuit module 41, (b) support element 36 is inserted into greater palatine canal 54, (c) circuit module 41 is placed against an alveolar process 68 of the maxilla, and (d) mucosa 58 is closed over circuit module 41. For implantation procedures during which a mucosal flap is raised, an approximately 5 mm incision is typically required to raise the mucosal flap. For some applications, the circuit module is coupled to the alveolar process, such as by using at least one nail or screw (coupling not shown).

Reference is made to FIGS. 6A-D, which are schematic illustrations of variable-length support elements 36, in accordance with respective embodiments of the present invention. In these embodiments, the length of support element 36 is adjustable during the implantation procedure, in order to accommodate differing lengths of greater palatine canal 54. It is noted that the variation in the length of the greater palatine canal in adults is generally less than +/−2 mm, so the length of support elements 36 in these embodiment need only vary by a relatively small percentage.

In the configuration shown in FIG. 6A, support element 36 is configured to allow telescopic coupling of a portion 80 of the support element. Electrode leads 84 pass through support element 36, including portion 80. The leads have sufficient slack so as to not interfere with the expansion and contraction of telescopic portion 80.

In the configuration shown in FIG. 6B, a portion of support element 36 is shaped so as to define one or more accordion pleats 82. Accordion pleats 82 are typically biased such that they are generally extended when in a relaxed position. Electrode leads 84 pass through support element 36, including the accordion portion. The leads have sufficient slack so as to not interfere with the expansion and contraction of accordion pleats 82. For some applications, support element 36 comprises a sleeve 88, which surrounds accordion pleats 82. The sleeve typically has a length no greater than the length of support element 36 when the support element is in its most contracted position, i.e., the sleeve surrounds only a portion of the non-accordion-pleated portion of the electrode leads. Such a length allows the total length of the support element to vary without being constrained by the length of the sleeve. Sleeve 88 typically comprises a flexible, biocompatible material, such as silicone. Sleeve 88 typically has a length less than 28 mm, e.g., less than 26 mm. Alternatively, for some applications, electrode leads 84 are accordion-pleated, in which case the electrode leads serve as support element 36.

In the configuration shown in FIG. 6C, electrode leads 84 are helically wound, so as to form a spring 86. The spring is typically biased so as to have an expanded resting position. For some applications, support element 36 comprises sleeve 88, which surrounds spring 86. The sleeve typically has a length no greater than the length of support element 36 when the support element is in its most contracted position, i.e., the sleeve surrounds only a portion of the non-helically-wound portion of the electrode leads. Such a length allows the total length of the support element to vary without being constrained by the length of the sleeve.

In the configuration in FIG. 6D, electrode leads 84 are shaped to as to define at least one omega-shaped portion 90. Portion 90 is typically biased so as to have extended resting positions. For some applications, support element 36 comprises sleeve 88, as described above with reference to FIGS. 6B and 6C.

Reference is made to FIGS. 7A-B, which are schematic illustration of oral element 32, in accordance with respective embodiments of the present invention. Oral element 32 is adapted to be placed in oral cavity 52 in a vicinity of implanted circuitry 40 of stimulator 30, e.g., in a vicinity of or in contact with the roof of the oral cavity. Oral element 32 typically comprises a power source 72, such as a rechargeable or disposable battery, circuitry 73, and at least one wireless coupling element 74. Depending on the specific application, wireless coupling element 74 transmits energy and/or data to circuitry 40, as described hereinbelow. For some applications, wireless coupling element 74 comprises a relatively large coil or a plurality of smaller coils, which may increase the likelihood that at least some portion of the generated magnetic field achieves good wireless coupling with implanted circuitry 40 of stimulator 30, even if oral element 32 is not precisely positioned or aligned with respect to stimulator 30, or if oral element 32 moves slightly after it has been placed against the roof of the oral cavity. For some applications in which wireless coupling element 74 comprises a plurality of coils, the coils are oriented with respect to one another such that the respective axes of the coils are not parallel with one another. For example, the coils may be oriented such that two or three of the axes are approximately orthogonal with one another.

In the embodiment shown in FIG. 7A, oral element 32 is adapted to be temporarily placed in oral cavity 52, without mechanically coupling the oral element to a surface of the oral cavity. For some applications, oral element 32 is coupled to an oral appliance, as described hereinbelow with reference to FIG. 8. In the embodiment shown in FIG. 7B, oral element 32 is adapted to be fixed to the roof of oral cavity 52, such as by using one or more screws 70, nails, or other surgical fastening devices.

FIG. 8 is a schematic illustration of oral element 32 coupled to an oral appliance 92, in accordance with an embodiment of the present invention. Oral appliance 92, which is typically shaped generally similarly to an orthodontic retainer, is configured to hold the oral element in a vicinity of or in contact with the roof of the oral cavity in a vicinity of implanted circuitry 40 of stimulator 30. The use of oral appliance 92, rather than mechanical coupling of oral element 32 to the roof of the oral cavity, generally reduces the likelihood of contamination. For some applications, oral appliance 92 is generally soft or semi-flexible, while for other applications, the oral appliance is generally rigid.

For some applications, oral element 32 does not comprise power source 72. Instead, power is provided by a power source located outside of the oral cavity. For example, the oral appliance may be coupled by a cable to an external driver comprising a power source. For some applications, the driver is coupled to a headset or necklace worn by the subject. The driver or a separate external control unit, instead of oral element 32, comprises all or a portion of circuitry 73. For some applications, the driver is coupled to external control unit 34, while for other applications, the driver comprises external control unit 34. Alternatively, oral element 32 is wirelessly coupled to external control unit 34, which may or may not be coupled to the external driver.

Reference is again made to FIGS. 5B-D. In the embodiment of the present invention shown in FIG. 5B, oral element 32 is configured to be coupled to a molar 98 or other tooth of the subject. For example, the oral element may comprise a clip or adhesive. Typically, the oral element is configured to be removably coupled to the tooth. For example, the oral element may be coupled to the tooth only during applications of stimulation by stimulator 30, and removed between applications of stimulation.

In the embodiment shown in FIG. 5C, oral element 32 is configured to be coupled to gingiva 99 covering alveolar process 68, and, optionally, to one or more teeth. For some applications, the oral element 32 is coupled to gingiva 99 using a clamp 101. Alternatively or additionally, the oral element is adapted to be held in place by the subject biting down on the element.

In the embodiment shown in FIG. 5D, oral element 32 comprises a capsule 200, which, for some applications, comprises power source 72 and circuitry 73. Oral element 32 further comprises an elongated connecting element 202, which couples capsule 200 to wireless coupling element 74. Capsule 200 is configured to be placed and held between alveolar process 68 and the inner surface of a cheek 204. For some applications, capsule 200 is generally cylindrical, similar in shape and size to a conventional dental cotton roll. Optionally, the capsule comprises a soft coating. Oral element 32 is configured such that wireless coupling element 74 is positioned on the lingual side of the teeth. For some applications, connecting element 202 passes over the occlusal surface of one or more teeth, as shown in FIG. 5D, while for other applications, connecting element 202 passes around the distal surface of the most distal molar (configuration not shown). Alternatively, connecting element 202 serves as wireless coupling element 74.

For some applications, capsule 200 does not comprise power source 72. Instead, power is provided by a power source located outside of the oral cavity. For example, the capsule may be coupled by a cable to an external driver comprising a power source. For some applications, the driver is coupled to a headset or necklace worn by the subject. The driver or a separate external control unit, instead of capsule 200, comprises all or a portion of circuitry 73. For some applications, the driver is coupled to external control unit 34, while for other applications, the driver comprises external control unit 34.

In an embodiment of the present invention, system 20 comprises a nasal element instead of or in addition to oral element 32 (configuration not shown). The nasal element is adapted to be inserted into a nostril of the subject, e.g., into the nasal vestibule. The nasal element comprises at least one wireless coupling element 74 that is wirelessly coupled to a transmit/receiver of stimulator 30, for transmitting/receiving power and/or data to/from the stimulator. In this embodiment, circuitry 40 of stimulator 30 is not necessarily positioned at the proximal end of the stimulator.

For some applications, circuitry 40 of stimulator 30 comprises a wireless coupling element. Wireless coupling element 74 of oral element 32 is adapted to wirelessly transmit energy and/or data to the wireless coupling element of circuitry 40, and/or to wirelessly receive data form the wireless coupling element of circuitry 40. For these applications, each of the wireless coupling elements typically comprises at least one coil. For some applications, the wireless coupling elements are wirelessly coupled to one another using induction, such as when the wireless coupling elements are positioned in close proximity to one another. Alternatively, the wireless coupling elements are wirelessly coupled to one another using RF energy, such as when the wireless coupling elements are positioned at a greater distance from each other. Further alternatively, the wireless coupling elements are wirelessly coupled to one another using another form of energy, such as ultrasound energy, in which case the wireless coupling elements comprises ultrasound transducers, e.g., piezoelectric transducers. “Transducer element,” as used in the present application including the claims, means an element adapted to wirelessly transmit and/or receive energy and/or data, including a coil, a piezoelectric transducer, and other wireless transducers known in the art.

In an embodiment of the present invention, oral element 32 does not comprise wireless coupling element 74. Instead, power source 72 of the oral element is coupled to circuitry 40 using a wire that passes through mucosa 58. The techniques of this embodiment are generally more energy-efficient than wireless energy/data transfer techniques. As a result, the battery of power source 72 of oral element 32 may need to be replaced or recharged less frequently, or not at all. For some applications, oral element 32 is adapted to be implanted in a tooth of the subject. For some applications, the implanted oral element comprises a wireless communication element for external wireless communication, such as of data. For some applications, power source 72 comprises a rechargeable or a replaceable battery.

Reference is made to FIG. 9, which is a schematic illustration of a contact-based energy transmission configuration of stimulation system 20, in accordance with an embodiment of the present invention. In this embodiment, a proximal end of support element 36 of stimulator 30 comprises a contact 94 that protrudes slightly from mucosa 58. Oral element 32 comprises a contact 96, which is brought into physical contact with contact 94 for transmitting power and/or data to/from circuitry 40. Contact 94 of stimulator 30 is typically in sealed contact with mucosa 58, in a similar manner to pacemaker leads. For some applications, contact 94 is typically semi-spherical in shape, as shown in FIG. 9. Alternatively, contact 94 is generally flat or concave in shape. The use of the contact-based techniques of this embodiment does not require alignment of oral element 32 with circuitry 40. In addition, the contact-based techniques of this embodiment result in a uniform, predictable transfer of energy, and are generally more energy-efficient than wireless energy/data transfer techniques. As a result, the battery of power source 72 of oral element 32 may need to be replaced or recharged less frequently, or not at all.

FIG. 10 is a schematic illustration of a configuration of contact 94, in accordance with an embodiment of the present invention. In this embodiment, contact 94 comprises positive and negative terminals 95 and 96, each of which is coupled to a respective lead 84. For some applications, support element 36, at a portion thereof which passes through mucosa 58, comprises a matrix 97, which is adapted to promote mucosal tissue growth therein. The growth of mucosal tissue in the matrix generally reduces the likelihood of infection, and helps hold contact 94 in place. For some applications, contact 94 and/or matrix 97 is coated with an antiseptic substance, such as an antibacterial substance, to reduce the likelihood of infection passing from the oral cavity through the mucosa.

Reference is made to FIG. 11A, which is a schematic illustration of energy and data transmission paths between components of system 20, in accordance with an embodiment of the present invention. Typically, wireless coupling element 74 of oral element 32 is adapted to wirelessly transmit energy to circuitry 40 of stimulator 30, for powering the stimulator, as symbolically indicated by an arrow 100. The close proximity of the wireless coupling elements of oral element 32 and stimulator 30 generally allows the use of relatively low energy levels and/or a small receiving element in circuitry 40, e.g., a small coil or piezoelectric transducer.

In an embodiment of the present invention, the energy transmitted to circuitry 40 of stimulator 30 does not include the stimulation waveform to be applied using electrodes 38. Instead, energy is typically transferred using a continuous wave (i.e., electromagnetic energy of constant amplitude and frequency). Circuitry 40 of stimulator 30 is configured to generate the stimulation waveform applied by electrodes 38. Alternatively, the energy is transferred using a quasi-continuous wave, which encodes data, which data is used by circuitry to generate the stimulation waveform applied by electrodes 38. The techniques of this embodiment may be employed, for example, with the configurations of stimulation system 20 described hereinabove with reference to FIGS. 1 and/or 8, and/or hereinbelow with reference to FIGS. 12-14 and/or 15. The transfer of energy only, in accordance with this embodiment, generally allows complete control of the waveform delivered by electrodes 38, because the generation of the waveform is independent of the wireless coupling of oral element 32 and circuitry 40 of stimulator 30. Furthermore, for some applications, circuitry 40 generates a bipolar waveform, which typically reduces the total accumulated charge in the tissue, thus improving safety and electrode life span.

For some applications, wireless coupling element 74 of oral element 32 is additionally configured to transmit and/or receive data to/from circuitry 40 of stimulator 30, as indicated by an arrow 102. Such data typically includes stimulation control signals, parameters, and/or feedback information. Such data is typically transmitted only periodically, rather than constantly during stimulation. Circuitry 40 of stimulator 30 configures at least a portion of the stimulation parameters based on the received information. For these applications, circuitry 40 of stimulator 30 is configured to generate the stimulation waveform applied by electrodes 38, based on the configured parameters.

For some applications, wireless coupling element 74 of oral element 32 (either the same wireless coupling element used for transmitting and receiving data to and from circuitry 40 of stimulator 30, or a separate wireless coupling element) is adapted to wirelessly relay the data to and receive data from external control unit 34 (as indicated by an arrow 104), which also comprises a wireless coupling element 106. Typically, but not necessarily, substantive processing and generation of the data is performed exclusively by external control unit 34, rather than by oral element 32. For some applications, wireless coupling element 74 combines the data and the energy transmitted to circuitry 40 of stimulator 30 into a single signal, such as by modulating the data onto the carrier frequency of the transmitted energy, in which case circuitry 40 demodulates the received signal to obtain the data. Alternatively, wireless coupling element 74 transmits the data and the energy in separate signals. Alternatively, for some applications, circuitry 40 of stimulator 30 is configured to transmit and/or receive all or a portion of the data directly to/from external control unit 34 (as indicated by an arrow 108), bypassing oral element 32, such as by using a VHF signal.

For some applications in which the energy is transferred using a continuous wave, the energy is transferred from outside the body of the subject, e.g., from a vicinity of the cheek or ear of the subject, rather than from oral element 32. This is possible because the continuous wave generally has low peak power levels. For these applications, system 20 typically does not comprise oral element 32.

In an embodiment of the present invention, circuitry 73 of oral element 32 generates the stimulation waveform, and wirelessly transmits the waveform to circuitry 40 of stimulator 30. For these applications, circuitry 40 of stimulator 30 is generally passive, and simply relays the received waveform to electrodes 38 with minimal or no processing. Circuitry 40 typically comprises a simple circuit, including one or more rectifiers and capacitors. The techniques of this embodiment may be employed, for example, with the configurations of stimulation system 20 described hereinabove with reference to FIGS. 1, 8, and/or 9.

For some applications, system 20 is configured to perform a calibration procedure in which the absolute energy level of the applied waveform is determined, and adjusted appropriately to achieve a desired stimulation level. Such calibration compensates for the patient-to-patient variability in energy transfer, caused, for example, by differences in placement and/or orientation of oral element 32 or circuitry 40 of stimulator 40, and/or inter-patient anatomical differences, e.g., thickness of the mucosa.

Reference is made to FIG. 11B, which is a schematic illustration of energy and data transmission paths between components of system 20, in accordance with an embodiment of the present invention. Except as described hereinbelow, this embodiment is similar to the embodiment described hereinabove with reference to FIG. 11A. In this embodiment, system 20 additionally comprises an external driver 110, which comprises power source 72 and circuitry 73. Oral element 32 comprises wireless coupling element 74, but typically does not comprise power source 72 or circuitry 73 (the oral element and/or the wireless coupling element may comprise minimal circuitry, such as one or more rectifiers or capacitors). Oral element 32 is electrically coupled to external driver 110 by an elongated flexible coupling element 112, which comprises one or more wires. Driver 110 is typically adapted to be physically coupled to a body of the subject, such as by being coupled to headset or a necklace.

Driver 110 typically comprises a wireless coupling element 114, which the driver uses to wirelessly relay data to and receive data from external control unit 34 (as indicated by an arrow 116). For example, the data may be transmitted using the Bluetooth protocol or another wireless communication protocol, or using an infrared signal. Alternatively, driver 110 is coupled to external control unit 34 by one or more wires (configuration not shown).

Reference is made to FIG. 12, which is a schematic illustration of a neural stimulation system 120, in accordance with an embodiment of the present invention. Except as noted hereinbelow, elements of system 120 are the same as corresponding elements of system 20 having the same reference numerals. System 120 comprises implantable neural stimulator 30 and external control unit 34. Stimulator 30 comprises elongated support element 36, one or more electrodes 38 fixed to the support element in the vicinity of the distal end thereof, and an implantable submucosal antenna 122 coupled to the support element in a vicinity of the proximal end thereof. Submucosal antenna 122 is adapted to be implanted in the roof of oral cavity 52 between oral mucosa 58 and a palate, e.g., hard palate 50 and/or a soft palate 134, and to generally conform to the shape of the palate.

FIG. 13 is a schematic illustration of implantable submucosal antenna 122, in accordance with an embodiment of the present invention. Submucosal antenna 122 comprises a thin, flexible sheet 124, which comprises at least one coil 126. Sheet 124 comprises a flexible biocompatible material, such as silicone.

Reference is made to FIG. 14A, which is a schematic illustration of energy and data transmission paths between components of system 120, in accordance with an embodiment of the present invention. System 120 typically lacks oral element 32 of system 20. Instead, external control unit 34 is adapted to transmit power, typically using RF energy, directly to submucosal antenna 122, for powering stimulator 30, as indicated by an arrow 140, and to transmit and/or receive data directly to/from the submucosal antenna, as indicated by an arrow 142. Such data typically includes stimulation control signals, parameters, and/or feedback information. Such data is typically transmitted only periodically, rather than constantly during stimulation. Circuitry 40 of stimulator 30 is configured to generate the stimulation waveform applied by electrodes 38, based on the configured parameters.

For some applications, wireless coupling element 106 combines the data and the energy into a single signal, such as by modulating the data onto the carrier frequency of the transmitted energy, in which case submucosal antenna 122 demodulates the received signal to obtain the data. Alternatively, wireless coupling element 106 transmits the data and the energy in separate signals. Alternatively, for some applications, stimulator 30 additionally comprises a wireless coupling element 144, to/from which external control unit 34 transmits and/or receives data, such as by using a VHF signal. Typically, external control unit 34 is adapted to be placed in a vicinity of a head of the subject, such as in a vicinity of an ear of the subject. For some applications, external control unit 34 is adapted to be coupled to the ear. For example, the control unit may comprise or be integrated into a wired or wireless headset, such as a cellular phone headset.

Reference is made to FIG. 14B, which is a schematic illustration of energy and data transmission paths between components of system 120, in accordance with an embodiment of the present invention. Except as described hereinbelow, this embodiment is similar to the embodiment described hereinabove with reference to FIG. 14A. In this embodiment, system 120 additionally comprises external driver 110, which comprises power source 72, circuitry 73, and at least one wireless coupling element 128. Driver 110 is typically adapted to be worn by the subject, such as by being coupled to headset or a necklace. Driver 110 is adapted to use wireless coupling element 128 to transmit power, typically using RF energy, directly to submucosal antenna 122, for powering stimulator 30, as indicated by an arrow 140, and to transmit and/or receive data directly to/from the submucosal antenna, as indicated by an arrow 142.

Driver 110 typically uses wireless coupling element 128, or a separate wireless coupling element (not shown), to wirelessly relay data to and receive data from external control unit 34 (as indicated by an arrow 130). For example, the data may be transmitted using the Bluetooth protocol or another wireless communication protocol, or using an infrared signal. Alternatively, driver 110 is coupled to external control unit 34 by one or more wires (configuration not shown).

Reference is made to FIG. 15, which is a schematic illustration of a configuration of stimulator 30 for use in stimulation system 120, described hereinabove with reference to FIGS. 12-14, in accordance with an embodiment of the present invention. In this embodiment, instead of submucosal antenna 122, system 120 comprises a coil antenna 160, at least a portion of which is coiled around at least a portion 162 of support element 36. Alternatively, coil antenna 160 is an integral part of portion 162. For some applications, coil antenna 160 comprises ferrite. For some applications, a sleeve is placed around all or a portion of coil antenna 160 and/or support element 36 (configuration not shown). Typically, the distal end of support element 36 comprises surgical punch 60, described hereinabove with reference to FIG. 1. For some applications, coil antenna 160 comprises a plurality of coils arranged in various orientations, which generally improves wireless coupling with wireless coupling element 106 of external control unit 34. For example, the plurality of coils may comprise two or three coils oriented approximately orthogonally to one another. In the configuration shown in FIG. 15, support element 36 and coil antenna 160 are typically adapted to be contained entirely within greater palatine canal 54.

Reference is made to FIG. 16, which is a schematic illustration of a configuration of electrodes 38, in accordance with an embodiment of the present invention. In this embodiment, electrodes 38 comprise at least one (e.g., exactly one) cathode 150, and at least one (e.g., exactly one) anode 152. Cathode 150 is typically located closer to a distal tip 154 of support element 36 than is anode 152. Typically, a length L1 of anode 152 is greater than a length L2 of cathode 150, such as at least 200% of length L2. A closest distance D1 between cathode 150 and anode 152 is typically greater than a closest distance D2 between any portion of cathode 150 and any portion of SPG 56.

In an embodiment of the present invention, a method for implanting stimulator 30 in greater palatine canal 54 comprises placing the stimulator in a bore of a needle having a sharp distal tip, passing the needle through mucosa 58 and greater palatine foramen 42, into canal 54, and withdrawing the needle, thereby leaving the stimulator implanted in the canal. Alternatively, the needle is first passed into canal 54, and stimulator 30 is subsequently introduced into the bore of the needle. The needle is typically passed through mucosa 58 without requiring a prior surgical incision in the mucosa, i.e., without requiring the use of a surgical knife or other tool. Alternatively, prior to insertion of the needle into the canal, a submucosal surface on the hard palate is prepared, such as by raising a mucosal flap, and/or by creating a mucosal opening using a retractor.

Reference is made to FIGS. 17A-C, which are schematic illustrations of an array 190 of electrodes 38, in accordance with an embodiment of the present invention. In this embodiment, stimulator 30 of system 20 or 120 comprises array 190, which typically comprises between about 8 and about 32 electrodes 38, such as about 32 electrodes. FIG. 17A shows array 190 in a flat, unrolled position. Typically, the array is organized in rows and columns, for example, between about 2 and about 8 rows, e.g., 8 rows, and between about 2 and about 4 columns, e.g., 4 columns. FIG. 17B shows array 190 encircling support element 36 (only a single column of electrodes 38 is visible in the figure). (For the sake of illustration, support element 36 is visible between electrodes 38 in FIG. 17B; in actual applications, a portion of the support element may be concealed by structural elements of array 190.) FIG. 17C is a cross-sectional top-view of one row of electrodes 38. For some applications, array 190 is fabricated on a flat substrate 192 (FIG. 17A), which is wrapped around support element 36 (FIG. 17B). For some applications, substrate 192 extends longitudinally along all or a portion of the length of support element 36, electrodes 38 are positioned in a distal region of the substrate, and circuitry of stimulator 30, such as circuitry 40, amplifier, and/or filters, is affixed to the substrate, e.g., in a proximal region of the substrate. For other applications, stimulator 30 does not comprise substrate 192, and electrodes 38 are coupled directly to, or are integral with, support element 36. It is noted that although stimulator 30 is generally shown in the figures as comprising array 190 of electrodes 38, this is for the sake of illustration only; embodiments described and shown herein may use the electrode configuration described hereinabove with reference to FIG. 16; electrode configurations described in U.S. patent application Ser. No. 10/783,113, issued as U.S. Pat. No. 7,117,033 to Shalev et al., such as with reference to FIG. 12, 13, or 14 thereof; electrode configurations described in the other patent applications incorporated by reference hereinbelow; or electrode configurations known in the art of neural stimulation.

In an embodiment of the present invention, stimulator 30 comprises a plurality of electrodes, at least a portion of which are adapted to be separately activatable. System 20 or 120 is adapted to use a calibration algorithm to activate, during a plurality of calibration periods, respective different sets of one or more of electrodes 38, in order to determine which set's activation causes a level of stimulation of the SPG closest to a desired level. For example, the desired level may be the maximum level that can be achieved for a given set of stimulation parameters. For some applications, the algorithm is alternatively or additionally used for setting a level of one or more stimulation parameters. System 20 or 120 typically uses the algorithm to determine the optimum set of electrodes after stimulator 30 has been implanted, so as to obviate the need to adjust the location of the stimulator after it has been implanted. Alternatively or additionally, the position of stimulator 30 is adjusted responsively to information derived using the algorithm. For some applications, during post-calibration (i.e., therapeutic) stimulation, the system activates different sets of electrodes at different times, such as in order to vary the level of stimulation applied to the SPG.

In an embodiment of the present invention, the level of stimulation of the SPG is determined by receiving feedback directly from the SPG, or from other neural tissue in a vicinity of the SPG, i.e., by using at least a portion of electrodes 38 to directly measure a level of stimulation of the SPG or the other neural tissue at or in a vicinity of the site(s) of the stimulation by the electrodes. For some applications, the at least a portion of electrodes 38 measure an electrical field of nervous tissue of the SPG or the other neural tissue induced by the electrical stimulation of the SPG. Typically, the signal generated by the sensed field is filtered to remove any artifacts in the signal generated by the stimulation applied by electrodes 38.

For some applications, the same set of one or more electrodes applies stimulation and measures the achieved stimulation of the SPG, by measuring the level of stimulation of the SPG or the other neural tissue. For other applications, a first set of one or more electrodes applies the stimulation, and a second set of one or more electrodes measures the achieved stimulation. Typically, the second set of electrodes is located in a vicinity of the first set of electrodes, and/or adjacent to the first set of electrodes in array 190.

Alternatively or additionally, for some applications, the level of stimulation of the SPG is determined by assessing an indirect physiological parameter of the subject related to the level of SPG stimulation, such as cerebral blood flow (CBF) and/or BBB permeability. For some applications, assessment techniques described hereinbelow are used. For some applications, a healthcare worker enters the values of the indirect physiological parameter into system 20, while for other applications, a device for measuring the indirect physiological parameters is coupled to system 20, and communicates the parameters to the system.

For some applications, system 20 is configured to select the desired set of electrodes 38. Alternatively or additionally, system 20 comprises an output unit, such as a display, which presents the results of the calibration algorithm to a healthcare worker, who selects the desired set of electrodes.

In an embodiment of the present invention, stimulator 30 is autonomically powered, such as by utilizing temperature differentials within the subject, e.g., using techniques described in the above-mentioned U.S. Pat. No. 6,470,212 to Weijand et al. and U.S. Pat. No. 6,640,137 to MacDonald, mutatis mutandis, or other techniques known in the art for generating energy from biological processes for powering an implanted medical device. For some applications, circuitry 40 of stimulator 30 does not comprise a wireless coupling element, or the wireless coupling element is used only for data transmission, rather than for wirelessly receiving energy. In the latter case, data is typically transmitted from and/or to external control unit 34.

In an embodiment of the present invention, electrodes 38 are located in a vicinity of a proximal end of support element 36, such that the electrodes apply electrical stimulation to greater palatine nerve 66 in a vicinity of the proximal opening of greater palatine foramen 42. For example, a closest distance between the electrodes and the proximal opening of the greater palatine foramen may be less than 10 mm, e.g., less than 5 mm. For some applications, upon implantation of stimulator 30, electrodes 38 are contained entirely within greater palatine canal 54, while for other applications, all or a portion of the electrodes are located submucosally outside of the canal and the foramen.

Although electrodes 38 have been described as being applied to an SPG of the subject, for some applications the electrodes are applied to another MTS of the subject, as defined hereinabove. For some of these applications, electrodes 38 are passed through the greater palatine canal to the MTS, while for other applications the electrodes are passed through only a portion of the greater palatine canal, or are advanced to the MTS by another route.

FIG. 18 a schematic pictorial view of a stimulation system 500, for stimulation of a sphenopalatine ganglion (SPG) system, as defined hereinabove, and/or at least one other appropriate “modulation target site” (MTS), as defined hereinabove, such as SPG 56, in accordance with an embodiment of the present invention. Stimulation system 500 comprises a support element 510, which typically, but not necessarily, is generally rigid (i.e., it generally keeps its original shape during a placement procedure). A distal end 512 of support element 510 comprises one or more electrodes 514. For some applications, electrodes 514 are recessed within support element 510, as shown in the figure, while for other applications the electrodes are flush with the surface of the support element, or protrude therefrom. Alternatively, the electrodes are configured as shown in FIGS. 13 and 14 of U.S. patent application Ser. No. 10/783,113, issued as U.S. Pat. No. 7,117,033 to Shalev et al.

Support element 510 is adapted to be inserted into a vicinity of an MTS or an SPG system of the subject, as defined hereinbelow, via a greater palatine canal in a roof of an oral cavity of the subject. Typically, support element 510 is substantially straight. Support element 510 typically comprises one or more marks 516 that indicate the point at which the support element has been sufficiently inserted into the greater palatine canal. Alternatively or additionally, support element 510 comprises a stopper (not shown) in a vicinity of marks 516, that mechanically prevents further insertion of the support element into the canal.

Stimulation system 500 further comprises a semi-flexible oral appliance 518, which is physically coupled to support element 510 by flexible leads 520. Oral appliance 518 comprises a neurostimulator 522, which is electrically coupled to electrodes 514 via leads 520. An upper surface 524 of oral appliance 518 is shaped to fit closely to the roof of the oral cavity, and is adapted to be coupled thereto. For example, oral appliance 518 may be shaped generally similarly to an orthodontic retainer. Neurostimulator 522 is typically battery-powered, and configurable to drive electrodes 514 to stimulate the MTS or SPG system. For some applications, the subject himself activates neurostimulator 522. Stimulation system 500 is typically adapted to remain in the oral cavity for between several hours and about two days.

In an embodiment of the present invention, a stimulation system for application to a subject comprises an elongated support element having a length of between about 1.8 cm and about 4 cm, such as a length of between about 1.8 cm and about 3 cm. The support element comprises one or more electrodes fixed thereto in a vicinity of a distal end thereof. The stimulation system further comprises a control unit, coupled to the support element in a vicinity of a proximal end thereof. The control unit typically comprises a battery, and is adapted to drive the electrodes to apply an electrical current to tissue of the subject, such as the SPG system and/or at least one MTS. The control unit typically configures the current to have a pulse frequency of between about 10 Hz and about 50 Hz, an amplitude of between about 0.2 V and about 10 V, a pulse width of between about 50 microseconds and about 5 milliseconds, and, in alternation, on periods of between about 1 second and about 2 minutes, and off periods of between about 1 second and about 2 minutes. (Together, the on and off periods define a duty cycle.) For example, the control unit may drive the electrodes to apply the current having on periods of between about 60 seconds and about 105 seconds, and off periods of between about 30 seconds and 90 seconds, e.g., on periods of about 90 seconds, and off periods of about 60 seconds.

For some applications, the support element is semi-rigid. For example, the support element and the electrodes together may be similar to conventional concentric needle electrodes, such as Medtronic, Inc. needle electrode model DCN50, or Oxford Instruments Plc. needle electrode models X53153, X53155, X53156, X53158, or X53159.

For some applications, the stimulation system comprises an oral appliance, coupled to the support element, and shaped so as to define a surface that fits closely to a roof of an oral cavity. For example, the oral appliance may be similar to oral appliance 518, described hereinabove with reference to FIG. 18. For some applications, the control unit has a volume, including the battery, of less than about 3 cm³.

In an embodiment of the present invention, a stimulation system for application to a subject comprises an elongated support element having a length of between about 1.8 cm and about 4 cm, such as a length of between about 1.8 cm and about 3 cm. The support element comprises one or more electrodes fixed thereto in a vicinity of a distal end thereof, and a receiver, fixed to the support element in a vicinity of the proximal end thereof. The stimulation system further comprises a control unit, adapted to be coupled to the receiver. The control unit is adapted to drive the electrodes via the receiver to apply an electrical current to tissue of the subject, such as the SPG system and/or at least one MTS. The control unit typically configures the current to have a pulse frequency of between about 10 Hz and about 50 Hz, an amplitude of between about 0.2 V and about 10 V, a pulse width of between about 50 microseconds and about 5 milliseconds, and, in alternation, on periods of between about 1 second and about 2 minutes, and off periods of between about 1 second and about 2 minutes. (Together, the on and off periods define a duty cycle.) For example, the control unit may drive the electrodes to apply the current having on periods of between about 60 seconds and about 105 seconds, and off periods of between about 30 seconds and 90 seconds, e.g., on periods of about 90 seconds, and off periods of about 60 seconds.

For some applications, the receiver comprises an electrical contact site, and the control unit is adapted to be coupled to the receiver by being brought into physical contact with the electrical contact site. For example, the control unit may be brought into physical contact by positioning the control unit inside an oral cavity of the subject. For some applications, the stimulation system comprises an oral appliance, adapted to be fixed to the control unit, and shaped so as to define a surface that fits closely to a roof of an oral cavity. For example, the oral appliance may be similar to oral appliance 518, described hereinabove with reference to FIG. 18.

Alternatively, the receiver comprises a transducer, and the control unit comprises a wireless transmitter, which is adapted to couple the control unit to the receiver via wireless electromagnetic communication with the transducer. Typically, the transducer comprises a coil. For some applications, the control unit is adapted to be positioned outside of a head of the subject. Alternatively, the control unit is adapted to be placed in the oral cavity, such as by being fixed to an oral appliance. For some applications, the receiver has a volume of less than about 0.8 cm³, such as less than about 0.15 cm³.

For some applications, stimulator 30 is implanted using techniques described in a U.S. Pat. No. 7,636,597, entitled, “Surgical tools and techniques for stimulation,” which is assigned to the assignee of the present application and is incorporated herein by reference.

In the present patent application, “SPG system” means the SPG and associated neuroanatomical structures, including neural tracts originating in or reaching the SPG, including outgoing and incoming parasympathetic and sympathetic tracts, which tracts include preganglionic fibers of the SPG (e.g., fibers contained within the vidian nerve) and postganglionic fibers of the SPG (fibers that travel anterogradely from the SPG toward the brain vascular bed, including the retro-orbital branches of the SPG, which are fibers that connect the SPG with orbital neural structures).

In an embodiment of the present invention, during placement of electrodes 38 at an MTS, as defined hereinabove, at least one physiological indicator of cerebral blood flow (CBF) is observed or measured concurrently with or after placement. For some applications, optimization of placement of electrodes 38 onto the appropriate neural structure is performed by activating the stimulator, and generally simultaneously monitoring CBF while manipulating the electrodes, and/or adjusting at least one parameter of the applied stimulation, so as to increase or decrease CBF, as appropriate. Alternatively or additionally, this technique is used to verify the placement of electrodes 38 after implantation, and/or to select which combination of electrodes to use, such as by using the feedback algorithm described hereinabove. Alternatively or additionally, a similar optimization process is performed, either during or after placement of electrodes 38, to determine parameters of the applied current so as to achieve a desired effect, e.g., on CBF or BBB permeability, as indicated by CBF.

Physiological indicators of CBF include, but are not limited to, the following:

-   -   a measure of vasodilation of blood vessels of the eye,         determined by unaided visual inspection or by using an         instrument, e.g., an instrument comprising machine vision         functionality;     -   transcranial Doppler ultrasonography measurements;     -   a measure of forehead perfusion, measured, for example, using         laser Doppler perfusion imaging (LDI) and/or using a temperature         sensor; and/or     -   near infrared spectroscopy (NIRS) measurements.

Other appropriate measurements indicative of CBF for use with these embodiments of the present invention will be apparent to those skilled in the art, having read the disclosure of the present patent application.

For some applications, one or more of the devices described hereinbelow with reference to FIGS. 18-21 are used for assessing a physiological indicator of CBF.

FIG. 19 is a schematic illustration of a vasodilation measurement instrument 230, in accordance with an embodiment of the present invention. Instrument 230 comprises an image sensor 234 (e.g., a CCD or CMOS sensor, or another camera) and processing circuitry 238, in order to provide machine vision functionality. Image sensor 234 is directed towards an eye 232 of the subject. The instrument measures the ratio of red to white in the sclera of eye 232, or another indication of vasodilation.

FIG. 20 is a schematic illustration of a laser Doppler perfusion (LDI) device 270, in accordance with an embodiment of the present invention. LDI device 270 comprises a laser source 271, a scanner 272, and a computer 281. Scanner 272 is positioned near a forehead 241 of the subject for measuring forehead perfusion.

FIG. 21 is a schematic illustration of a thermometer 280, in accordance with an embodiment of the present invention. Thermometer 280 is positioned touching a forehead 241 of the subject for measuring forehead perfusion.

FIG. 22 is a schematic illustration of a transcranial Doppler ultrasonography device 284, in accordance with an embodiment of the present invention. Transcranial Doppler ultrasonography device 284 is positioned touching a head 288 of the subject for measuring CBF.

For some applications, the measurement device, such as those described hereinabove with reference to FIGS. 18-21, comprises an output unit 236, such as a numeric display, tone generator, color display, or other output device, for outputting a signal indicative of the measured physiological parameter. Alternatively or additionally, instrument 230 is coupled to an internal or external control unit of system 20 or 120, and communicates the signal directly to the control unit.

In an embodiment of the present invention, during placement of electrodes 38 at an MTS, as defined hereinabove, penetration of a systemically administered dye into an eye of the subject is observed or measured concurrently with or after placement, as an indication of a level of increased permeability of the BBB. For example, the dye may include fluorescein dye. For some applications, optimization of placement of electrodes 38 onto the appropriate neural structure is performed by activating the stimulator, and generally simultaneously monitoring the penetration of the dye while manipulating the electrodes, and/or adjusting at least one parameter of the applied stimulation, so as to increase or decrease permeability of the BBB, as appropriate. Alternatively or additionally, this technique is used to verify the placement of electrodes 38 after implantation, and/or to select which combination of electrodes to use, such as by using the feedback algorithm described hereinabove. Alternatively or additionally, a similar optimization process is performed, either during or after placement of electrodes 38, to determine parameters of the applied current so as to achieve a desired effect, e.g., on CBF or BBB permeability, as indicated by BBB permeability.

In an embodiment of the present invention, one or more of the above-described CBF-based assessment techniques are used by a healthcare worker after implantation to assess (a) whether electrodes 38 retain appropriate placement and contact with the MTS, and/or (b) whether parameters of the applied current (e.g., magnitude, frequency, duration, scheduling) continue to achieve the desired effect, e.g., on CBF or BBB permeability. For example, such an assessment may be performed periodically during post-implantation follow-up care.

In an embodiment of the present invention, the CBF-based assessment techniques described hereinabove are used to assist in determining the effective dosage and/or other parameters for presenting odorants to an air passage of the patient, as described in U.S. patent application Ser. No. 10/512,780, published as US Patent Application Publication 2005/0266099, filed Oct. 25, 2004, which is assigned to the assignee of the present application and is incorporated herein by reference.

In an embodiment of the present invention, chemical stimulation of at least one MTS is achieved by presenting chemicals, for example in a liquid or gaseous state, to an air passage of the subject, such as a nasal cavity or a throat, or in a vicinity thereof. The temporal profile and other quantitative characteristics of such chemical modulation are believed by the present inventors to have a mechanism of action that has a neuroanatomical basis overlapping with that of the electrical modulation of the MTS. For some applications, chemical-presentation techniques described herein are practiced in combination with techniques described in U.S. patent application Ser. No. 10/512,780, published as US Patent Application Publication 2005/0266099, filed Oct. 25, 2004, and/or U.S. patent application Ser. No. 10/952,536, published as US Patent Application Publication 2005/0159790, filed Sep. 27, 2005, both of which are assigned to the assignee of the present patent application and are incorporated herein by reference. In these chemical-presentation applications, an extent to which the chemical has achieved the desired effect (e.g., increased permeability of the BBB, or increased or decreased CBF) is determined by monitoring real-time changes in CBF, and adjusting the dose of the chemical responsive thereto.

Chemicals that may increase or decrease cerebral blood flow and/or the permeability of the blood-brain barrier (e.g., via modulation of SPG-related fibers), include, but are not limited to, propionic acid, cyclohexanone, amyl acetate, acetic acid, citric acid, carbon dioxide, sodium chloride, ammonia, menthol, alcohol, nicotine, piperine, gingerol, zingerone, allyl isothiocyanate, cinnamaldehyde, cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate, thymol, and eucalyptol. The chemicals reach the appropriate neural structures and induce vasodilatation, vasoconstriction and/or cerebrovascular permeability changes.

In an embodiments of the present invention, chemical stimulation is applied to at least one MTS, using (a) a nasal applicator adapted to deliver the stimulating chemical to an upper region of the nasal cavity, or (b) a transpalatine applicator inserted via the greater palatine canal.

In some embodiments of the present invention, stimulation of at least one MTS is achieved by applying a neuroexcitatory agent to the MTS. Suitable neuroexcitatory agents include, but are not limited to, acetylcholine and urocholine. For some applications, the MTS is stimulated by applying a neuroinhibitory agent, such as atropine, hexamethonium, or a local anesthetic (e.g., lidocaine). In these agent-application embodiments, an extent to which the agent has achieved the desired effect (e.g., increased permeability of the BBB, or increased or decreased CBF) is determined by monitoring real-time changes in CBF, and adjusting the dose of the agent responsive thereto.

In an embodiment of the present invention, stimulation of the MTS is achieved by applying mechanical stimulation to the MTS, e.g., vibration. An extent to which the mechanical stimulation has achieved the desired effect (e.g., increased permeability of the BBB, or increased or decreased CBF) is determined by monitoring real-time changes in CBF, and adjusting the extent of the mechanical stimulation (e.g., magnitude, frequency, or duration) responsive thereto.

It is also to be appreciated that whereas some embodiments of the present invention are described with respect to implanting the electrical stimulator, for some applications the stimulator is temporarily inserted into the subject, and techniques described herein are used to optimize the temporary placement of the stimulator.

In an embodiment of the present invention, bilateral stimulation is applied, in which a first electrode is applied to a first MTS, and a second electrode is applied to a second MTS. Such bilateral stimulation may be applied using techniques described in U.S. Provisional Patent Application 60/604,037, filed Aug. 23, 2004, which is assigned to the assignee of the present application and is incorporated herein by reference, and/or in PCT Patent Application PCT/IL2005/000912 (published as PCT Publication WO 06/021957), filed Aug. 23, 2005,“entitled, “Concurrent bilateral SPG modulation,” which is assigned to the assignee of the present application and is incorporated herein by reference.

FIG. 23A is a schematic illustration of a nasal magnetic induction device 400, in accordance with an embodiment of the present invention. Nasal magnetic induction device 400 generates a magnetic field in the vicinity of an MTS. The magnetic field induces an electric current in the MTS, which temporarily depolarizes neurons therein, thereby electrically stimulating the MTS. Nasal magnetic induction device 400 typically comprises a wire coil 410 adapted to be insertable into the nasal cavity, and a control unit 412 coupled to the coil. As appropriate, the coil may be compressed during insertion and expand at the target site, or it may be retracted during insertion within a supporting element 414 of device 400, and released when at the target site. Typically, coil 410 has a diameter D of between about 3 mm and about 12 mm, and comprises between about 4 and about 30 loops of wire. The wire typically has a diameter of between about 50 micrometers and about 200 micrometers. Upon activation, the control unit generates a pulsed electric current in the coil. Because of the close proximity of the coil to an MTS, e.g., an SPG, the control unit typically outputs power sufficient to stimulate the SPG but generally insufficient to substantially stimulate surrounding peripheral or brain tissue. For some applications, the nasal magnetic induction device further comprises a cooling element (e.g., a thermoelectric cooling element, a liquid cooling mechanism, or an air cooling mechanism), which is adapted to prevent excessive heating of the coil.

FIG. 23B is a schematic illustration of a nasal magnetic induction device 420, in accordance with an embodiment of the present invention. Nasal magnetic induction device 420 is similar to nasal magnetic induction device 400, described hereinabove with reference to FIG. 23A, except that nasal magnetic induction device 420 comprises a figure-eight-shaped wire coil 430, which may, for example, enhance focusing of the induced field. Alternatively, nasal magnetic induction device 420 comprises a 4-leaf-shaped wire coil, such as described in the above-cited article to Roth B J et al.

FIGS. 24A and 24B are schematic illustrations of an external magnetic induction device 440, in accordance with an embodiment of the present invention. External magnetic induction device 440 comprises (a) one or more (typically two) magnetic coils 450 adapted to be placed in a vicinity of a temporomandibular joint 452 of a subject, in a vicinity of an MTS, e.g., an SPG, and (b) a control unit 454 coupled to the coils. Typically, each coil 450 has a diameter of between about 30 mm and about 120 mm, and comprises between about 4 and about 30 loops of wire.

In an embodiment of the present invention, an external magnetic induction device comprises a coil adapted to be placed partially or completely around a head of the subject (not necessarily in the configuration shown in FIGS. 24A and 24B), and a control unit coupled to the coil. Typically, the coil has a diameter of between about 3 cm and about 12 cm, and comprises between about 4 and about 30 loops of wire. The coil is configured to focus the generated magnetic field on at least one MTS, e.g., the SPG.

FIG. 25 is a schematic pictorial view of an electrical stimulation system 310 comprising an implantable stimulator 312, for stimulation of a “modulation target site” (MTS), as defined hereinabove, such as a sphenopalatine ganglion (SPG) 322, in accordance with an embodiment of the present invention. In FIG. 25, a human nasal cavity 320 is shown, and stimulator 312 is implanted between the hard palate and the mucoperiosteum (not shown) of the roof of the mouth. Branches of parasympathetic neurons coming from SPG 322 extend to the middle cerebral and anterior cerebral arteries (not shown). Typically, one or more relatively short electrodes 326 extend from stimulator 312 to contact or to be in a vicinity of an MTS, such as SPG 322.

For some applications, stimulator 312 is implanted on top of the bony palate, in the bottom of the nasal cavity. Alternatively or additionally, the stimulator is implanted at the lower side of the bony palate, at the top of the oral cavity. In this instance, one or more flexible electrodes 326 originating in the stimulator are passed through the palatine bone or posterior to the soft palate, so as to be in a position to stimulate the SPG or another MTS. Further alternatively or additionally, the stimulator may be directly attached to the SPG and/or to another MTS.

For some applications, stimulator 312 is delivered to a desired point within nasal cavity 320 by removably attaching stimulator 312 to the distal end of a rigid or slightly flexible introducer rod (not shown) and inserting the rod into one of the patient's nasal passages until the stimulator is properly positioned. As appropriate, the placement process may be facilitated by fluoroscopy, x-ray guidance, fine endoscopic surgery (FES) techniques or by any other effective guidance method known in the art, or by combinations of the aforementioned. Typically, skin temperature and/or cerebral blood flow (CBF) is measured concurrently with insertion. CBF may be measured with, for example, a laser Doppler unit positioned at the patient's forehead or transcranial Doppler measurements. Verification of proper implantation of the electrodes onto the appropriate neural structure may be performed by activating the device, and generally simultaneously monitoring CBF.

For some applications, stimulator 312 is implanted using techniques described in U.S. patent application Ser. No. 10/535,024, filed Dec. 27, 2005, which issued as U.S. Pat. No. 7,636,597, entitled, “Surgical tools and techniques for stimulation,” which is assigned to the assignee of the present application and is incorporated herein by reference, and/or in the above-mentioned PCT Publication WO 04/043218. For some applications, techniques described herein are performed in combination with apparatus and/or methods that are described in U.S. patent application Ser. No. 11/349,020, filed Feb. 7, 2006, which issued as U.S. Pat. No. 7,561,919, entitled, “SPG stimulation via the greater palatine canal,” which is assigned to the assignee of the present application and is incorporated herein by reference.

FIG. 26 is a schematic illustration of a stimulator control unit 330 positioned external to a patient's body, in accordance with an embodiment of the present invention. At least one flexible electrode 332 typically extends from control unit 330, through a nostril of the patient, and to a position within the nasal cavity that is adjacent to SPG 322.

In an embodiment of the present invention, techniques described herein are performed in conjunction with techniques described in US Patent Application Publication 2004/0220644 (issued as U.S. Pat. No. 7,117,033), which is assigned to the assignee of the present application and is incorporated herein by reference. For example, the substantially rigid support element described therein may be initially quickly inserted into the stimulation site for acute treatment, and an implantable stimulator 312 may be subsequently implanted for longer-term treatment.

It is to be understood that electrodes 326 (FIG. 25) and 332 (FIG. 26) may each comprise one or more electrodes, e.g., two electrodes, or an array of microelectrodes. For applications in which stimulator 312 comprises a metal housing that can function as an electrode, typically one electrode 326 is used, operating in a monopolar mode. Regardless of the total number of electrodes in use, typically only a single or a double electrode extends to SPG 322. Other electrodes 326 or 332 or a metal housing of stimulator 312 are typically temporarily or permanently implanted in contact with other parts of nasal cavity 320.

Each of electrodes 326 and/or 332 typically comprises a suitable conductive material, for example, a physiologically-acceptable material such as silver, iridium, platinum, a platinum iridium alloy, titanium, nitinol, or a nickel-chrome alloy. For some applications, one or more of the electrodes have lengths ranging from about 1 to 5 mm, and diameters ranging from about 50 to 100 microns. Each electrode is typically insulated with a physiologically-acceptable material such as polyethylene, polyurethane, or a co-polymer of either of these. The electrodes are typically spiral in shape, for better contact, and may have a hook shaped distal end for hooking into or near the SPG. Alternatively or additionally, the electrodes may comprise simple wire electrodes, spring-loaded “crocodile” electrodes, or adhesive probes, as appropriate.

Reference is made to FIG. 27, which is a graph 600 illustrating electrical stimulation protocols, in accordance with an embodiment of the present invention. Excitatory stimulation of an MTS (e.g., the SPG) induces changes in CBF, induces the release of one or more neuroprotective substances, such as neuromodulators (e.g., nitric oxide (NO) and/or vasoactive intestinal polypeptide (VIP)), and/or modulates permeability of the blood-brain barrier (BBB). The inventors have found that excitatory stimulation of an MTS at at least a minimum threshold strength increases CBF, and that the increase in CBF is related to the strength of the stimulation. The inventors have also found that at a sufficiently high strength, such stimulation modulates the permeability of the BBB, in addition to increasing CBF.

“Strength,” as used in the present application, including the claims, means a total charge applied to an MTS in a given time period, e.g., one minute, one hour, or one day. Strength is increased or decreased by changing one or more parameters of the applied stimulation, such as the amplitude, number of cycles in a given time period, frequency, pulse width, or duty cycle (e.g., ratio of “on” to “off” time within a given cycle), as described hereinbelow in greater detail.

The y-axis of graph 600 indicates the strength of the stimulation of an MTS. The strength of the stimulation is determined by the values of the parameters of the stimulation, such as voltage, current, frequency, cycles per time period, and duty cycle. Stimulation at at least a minimum CBF-increasing strength 602 increases CBF. Stimulation at such a strength also typically induces the release of one or more neuroprotective substances, such as NO and/or VIP. A maximum CBF-increasing strength 606 is the strength at which CBF is maximally increased, i.e., further increases in strength do not further increase CBF. The BBB is opened, i.e., the permeability of the BBB to larger molecules or substances that do not cross the intact BBB is significantly increased, by stimulation having a strength in a range 608 between a minimum BBB-opening strength 610 and maximum BBB-opening strength 612 (beyond which increased strength does not result in additional opening of the BBB). Although minimum BBB-opening strength 610 is shown in graph 600 as being greater than maximum CBF-increasing strength 606, this is not necessarily the case.

In the present application, including the claims, stimulation of an MTS is considered capable of inducing a “significant” increase in the permeability of the BBB if the stimulation is capable of inducing at least one of the following:

(a) an increase in concentration of Evans blue (EB) in brain tissue of a subject, such as a rat, of at least 100% compared to a baseline concentration measured in a control rat. To determine the increase, permanent middle cerebral artery occlusion (pMCAO) is induced in the rat, such as using techniques described hereinbelow with reference to FIG. 30. Three hours after pMCAO, stimulation is applied to the MTS, and a bolus of EB 2% at 1 ml per kg body weight of the rat is administered intravenously. The rat is sacrificed one hour after application of the stimulation and administration of the EB. To determine the baseline concentration, pMCAO is induced in a control rat, three hours after pMCAO an identical EB bolus is administered intravenously, but no stimulation is applied, and the control rat is sacrificed one hour after the administration of the EB; and

-   -   (b) a serum S100beta level of the subject (indicative of         clearance of the protein from the brain into the systemic         circulation), at a measurement time 45 minutes after initiation         of MTS stimulation, that is at least 30% greater than a serum         S100beta level of the subject measured at the beginning of the         MTS stimulation.

Although the above are indications of the “significance” of an increase in permeability of the BBB, use of the apparatus and performance of the methods described and claimed herein typically do not include measuring any of these indications. In particular, indication (a) is generally only possible to measure in an animal model; if it were desired to conduct a human experiment, different techniques would likely be used, such as measuring the concentration in the brain of a radioactive isotope that is normally excluded by the BBB.

For some applications, it is desirable to apply stimulation to an MTS, and configure the stimulation to have a strength that induces an increase in permeability of the BBB that is even lower than a “significant” increase, as defined above. Such a “sub-significant” increase in permeability of the BBB is considered to occur if the stimulation is capable of inducing at least one of the following: (i) an increase in concentration of EB, under the conditions defined in indication (a) above, of at least 20%, such as at least 30%, e.g., at least 50%; and (ii) a serum S100beta level, under the conditions defined in indication (b) above, that is at least 10%, e.g., at least 20%, greater than the level of the subject measured at the beginning of the MTS stimulation.

For some applications, it is useful to define increased CBF as a percentage increase in CBF over a baseline level of CBF, which increase has at least a certain duration, e.g., at least 5 minutes. Typically, the baseline CBF level is either: (a) a normal baseline level for a subject, i.e., prior to an adverse brain event, such as a cerebrovascular event, e.g., a stroke, or (b) a post-event baseline level, prior to stimulation using the techniques described herein, and, optionally, prior to other treatment of the event. CBF is typically expressed as volume of blood flow per time per mass of the subject, e.g., ml/min/100 g. For some applications, increased CBF is expressed as an area under the curve (AUC) of CBF with respect to baseline over a certain time interval.

In an embodiment of the present invention, electrical stimulation system 310 is configured to apply excitatory electrical stimulation to at least one MTS of a subject, and to configure the stimulation to increase CBF of the subject and/or induce the release of neuroprotective substances, without substantially opening the BBB of the subject. In other words, the system sets the strength of stimulation equal to less than minimum BBB-opening strength 610, such as less than 90% of minimum BBB-opening strength 610, e.g., less than 80%, 70%, or 60% of minimum BBB-opening strength 610. For some applications, the system is configured to increase CBF of the subject and/or induce the release of neuroprotective substances without increasing the permeability of the BBB to a level that produces a measurably-harmful clinical effect for the subject.

For some applications, system 310 sets an acute strength 622 equal to a level appropriate for treatment of an acute condition, such as an adverse brain event (e.g., a cerebrovascular event), for which increased CBF and/or release of neuroprotective substances is beneficial, but for which opening the BBB is not indicated. For example, the system may set acute strength 622 equal to at least about 20% of minimum BBB-opening strength 610, e.g., at least about 50%, 60%, 70%, or 80% of minimum BBB-opening strength 610.

In an embodiment of the present invention, system 310 is used for rehabilitative treatment after an adverse brain event, such as a cerebrovascular event, e.g., a stroke, or for rehabilitative treatment of a non-acute cerebrovascular condition. Such rehabilitative stimulation induces the release of neuroprotective substances and/or maintains a slightly elevated level of blood flow, typically over an extended period of time, such as at least 24 hours, at least one week, at least two weeks, at least four weeks, or at least three months. As a result, such stimulation typically rehabilitates damaged tissue, improves perfusion of the rehabilitating brain, and/or accelerates angiogenesis. (See, for example, the above-mentioned article by Zhang R et al. (2001), which reports that NO donors administrated 24 hours after stroke significantly increased angiogenesis in the ischemic boundary regions.) For some applications, the system is configured to apply such rehabilitative stimulation intermittently, such as during one session per day, having a duration of between 1 minute and 6 hours, such as at least 5 minutes or at least 15 minutes, or between 2 and 4 hours, e.g., about 3 hours or about 6 hours, or more than 6 hours. Alternatively, the system is configured to apply such stimulation generally constantly, i.e., 24 hours per day. Further alternatively, the rehabilitative stimulation is applied less frequently than every day, such as once every other day (e.g., at least one minute during every 48 hours), or more frequently than once per day, such as during two sessions per day. For some applications, such stimulation is applied beginning at least one hour after the adverse brain event, such as a cerebrovascular event, e.g., a stroke, such as beginning at least 3 hours, at least 6 hours, at least 9 hours, at least 12 hours, at least 24 hours, or at least 48 hours after the brain event. For some applications, NO released by stimulation at rehabilitation strength 622 is of particular neuroprotective benefit during rehabilitation.

For some applications, such rehabilitative stimulation is applied during a plurality of stimulation periods which includes at least first and last stimulation periods. System 310 sets an inter-period interval between initiation of the first period and initiation of the last period to be at least 24 hours. For example, the first stimulation period may occur from 1:00 P.M. to 4:00 P.M. on a Monday, and the last stimulation period may occur from 1:00 P.M. to 4:00 P.M. on a Tuesday of the same week. Optionally, stimulation is applied during at least one additional stimulation period between the first and last periods. For example, stimulation may be additionally applied from 1:00 A.M. to 4:00 A.M. on the Tuesday. For some applications, the first period concludes simultaneously with the initiation of the last period, i.e., the stimulation is applied constantly from the beginning of the first period until the conclusion of the last period. For example, the stimulation may be applied constantly from 1:00 P.M. on Monday, January 1 to 4:00 P.M. on Tuesday, January 2, or constantly from 1:00 P.M. on Monday, January 1 to 4:00 P.M. on Monday, January 29. Alternatively, the initiation of the last stimulation period occurs after a conclusion of the first stimulation period, such that the stimulation is not applied during at least one non-stimulation period between the conclusion of the first stimulation period and the initiation of the last stimulation period.

For some applications, the system sets the inter-period interval to be at least 48 hours, such as at least one week, at least two weeks, or at least four weeks. When using such greater inter-period intervals, the system typically, but not necessarily, applies stimulation during at least several additional stimulation periods between the first and last stimulation periods. For some applications, such additional stimulation periods may include a plurality of daily stimulation periods, applied on every day between the initiation of the first stimulation period and the initiation of the last stimulation period. For example, the first stimulation period may occur from 1:00 P.M. to 4:00 P.M. on Monday, January 1, the last stimulation period may occur from 1:00 P.M. to 4:00 P.M. on Monday, January 8, and the additional daily stimulation periods may occur from 1:00 P.M. to 4:00 P.M. on each day from Tuesday, January 2 through Sunday, January 7, inclusive. For some applications, stimulation is applied for at least 30 minutes every day (e.g., at least 60 minutes every day) between the initiation of the first stimulation period and the initiation of the last stimulation period. For some applications, stimulation is applied during a plurality of non-continuous stimulation periods during each 24-hour period between the initiation of the first stimulation period and the initiation of the last stimulation period. For example, the first stimulation period may occur from 1:00 P.M. to 4:00 P.M. on Monday, the last stimulation period may occur from 1:00 P.M. to 4:00 P.M. on Wednesday, and stimulation may be applied during additional stimulation periods from (a) 1:00 A.M. to 4:00 A.M. on Tuesday, (b) from 1:00 P.M. to 4:00 P.M. on Tuesday, and (c) from 1:00 A.M. to 4:00 A.M. on Wednesday, such that stimulation is applied during two stimulation periods during the 24-hour period from 1:00 P.M. on Monday to 1:00 P.M. on Tuesday, and during two stimulation periods during the 24-hour period from 1:00 P.M. on Tuesday to 1:00 P.M. on Wednesday.

For some applications, the system is configured to set the inter-period interval to be no more than a maximum value, such as three, six, nine, or twelve months. For some applications, the system comprises a user interface, which enables a healthcare worker to enter a value for the inter-period interval. The system typically rejects values that are greater than the maximum value, such as by requiring the healthcare worker to enter another value, or by using the maximum value instead of the entered value. Alternatively, the system notifies the healthcare worker if the entered value is greater than the maximum value; optionally, the system allows the healthcare worker to override the notification.

For some applications, the system is configured to store a maximum total time of stimulation per each time period having a given duration, and to apply the stimulation no more than the maximum total time per each time period having the given duration. For example, the given duration of each time period may be 24 hours. Typical values for the maximum total time of stimulation per 24-hour period include one hour, three hours, six hours, ten hours, and twelve hours. For some applications, the maximum total time of stimulation is predetermined, e.g., by the manufacturer of the system, while for other applications, a healthcare worker enters the maximum total time of stimulation into the system.

As used in the present application, including the claims, a “stimulation period” includes an entire period during which stimulation is applied, even though current is applied to the site only during a portion of the period, because of the duty cycle, on/off periods, and/or frequency of the current, for example.

For some applications, system 310 sets the strength of stimulation during such long-term rehabilitation to a rehabilitation strength 620, such as between about 10% and about 40% of minimum BBB-opening strength 610, e.g., between about 20% and about 30% of minimum BBB-opening strength 610, or such as between about 10% and about 40% of maximum CBF-increasing strength 606, e.g., between about 20% and about 30% of maximum CBF-increasing strength 606. Alternatively or additionally, system 310 sets rehabilitation strength 620 to a level that causes an increase in CBF equal to less than about 40% of a maximum CBF increase that system 310 is capable of inducing.

In an embodiment of the present invention, system 310 sets the strength of stimulation to a preventive strength appropriate for preventing an occurrence of a brain event, typically a secondary brain event, e.g., a secondary stroke. For example, such strength may be between about 5% and about 50% of the minimum BBB-opening strength 610. For some applications, NO released by stimulation at the preventive strength is of particular neuroprotective benefit during prevention, and has an anti-thrombolytic, vasodilatory, and/or anti-inflammatory effect.

In an embodiment of the present invention, system 310 is configured to treat a complication of subarachnoid hemorrhage (SAH), such as a cerebral vasospasm. The currently-preferred conventional treatment for SAH includes a surgical procedure in which a medical vehicle is used to treat the SAH. The medical vehicle may comprise, for example: (a) a tool for treating the SAH such as by clipping the aneurysm that caused the SAH, and/or (b) a pharmaceutical treatment. However, the presence of blood in the subarachnoid space sometimes causes increased sensitization of large cerebral arteries, resulting at a later time in cerebral vasospasms. These late-onset vasospasms, in turn, cause brain ischemia and often irreversible damage (see the above-mentioned article by Van Gijn J et al.). Therefore, the stimulation of the MTS of this embodiment of the present invention is typically applied in conjunction with such a treatment (e.g., before, during or after the treatment), typically to the SPG, in order to counteract the reduced CBF sometimes caused by blood passage into the subarachnoid space.

Typically, for treating the complication of SAH, system 310 configures the stimulation to increase CBF of the subject and/or induce the release of neuroprotective substances, without substantially opening the BBB of the subject. Typically, system 310 is configured to set the strength of stimulation to at least acute strength 622, but no more than maximum CBF-increasing strength 606, so as not to substantially open the BBB. For some applications, the stimulation of the MTS is initiated at a time after the treatment when the hemorrhage has already been substantially reduced (at which time, in the absence of MTS stimulation, CBF is frequently reduced below desired levels). Alternatively, the stimulation of the MTS is initiated prior to this point, but generally has its strongest elevating effect on CBF once the hemorrhage has been substantially reduced.

Reference is again made to FIG. 27. In an embodiment of the present invention, electrical stimulation system 310 is configured to apply staged treatment of a brain event, such as an ischemic event (e.g., a stroke). The system configures the stimulation to dilate cerebral vessels, thereby increasing CBF to affected brain tissue and tissue in a vicinity thereof, and/or to induce the release of one or more neuroprotective substances, such as neuromodulators (e.g., nitric oxide (NO) and/or vasoactive intestinal polypeptide (VIP)). Such increased CBF and/or release of neuroprotective substances decrease damage caused by the brain event. The system is typically configured to adjust at least one parameter of the applied stimulation responsively to an amount of time that has elapsed since the occurrence of the brain event. For some applications, system 310 calculates the elapsed time responsively to an estimated time of occurrence of the brain event, which is entered into the system by a healthcare worker, typically early in the treatment of the event. In these applications, the system typically automatically progresses from stage to stage based on the elapsed time from the occurrence of the event. Alternatively, for some applications, a healthcare worker manually selects the stages.

System 310 is typically configured to apply the stimulation in two or more stages. For some applications, during a first, acute stage 630, the system sets the parameters of stimulation to acute strength 622, which is sufficient to cause a high level of cerebral vessel dilation and/or a release of neuroprotective substances, but insufficient to substantially open the BBB. Such stimulation is primarily intended to arrest the spreading of the initial ischemic core, such as by restoring blood flow to the penumbra in order to prevent damage to cells therein, and/or by releasing neuroprotective substances, such as NO and/or VIP. Such stimulation may also save some cells within the ischemic core, such as neuronal cells. The first stage of stimulation is typically appropriate during the period beginning at the time of the event, and ending at about 4 to 8 hours after the time of the event, such as at about 6 hours after the event. Alternatively, the first stage of stimulation is appropriate until about 24 hours after the time of the event. (See, for example, the above-cited articles by Davis S M et al. and Phan T G et al.) For some applications, VIP released by stimulation at acute strength 622 is of particular neuroprotective benefit. For some applications, hypoperfused areas of the brain are identified, such as by using MRI or PET, which can potentially be saved using the stimulation techniques described herein.

During a second, rehabilitative stage 636, system 310 reduces the strength of the stimulation to rehabilitation strength 620, and typically applies the stimulation intermittently, such as during one session per day, having a duration of between 1 minute and 6 hours, such as between 2 and 4 hours, e.g., about 3 hours, or more than 6 hours. This rehabilitative level of stimulation continues to induce the release of neuroprotective substances, and/or maintains a slightly elevated level of blood flow. This stage of stimulation is typically applied during the period beginning at the conclusion of acute stage 630, and lasting at least one week, such as at least two weeks, at least one month, at least three months, or at least six months. Alternatively, the rehabilitative stimulation is applied generally constantly, i.e., 24 hours per day. Further alternatively, the rehabilitative stimulation is applied less frequently than every day, such as once every other day, or more frequently than once per day, such during two sessions per day.

For some applications, system 310 is configured to apply stimulation during an additional, post-acute stage 632, between acute stage 630 and rehabilitative stage 636. During post-acute stage 632, the system reduces the strength of the stimulation to a post-acute strength 634, between acute strength 622 and rehabilitation strength 620. This post-acute strength is sufficient to maintain an increased level of blood flow to and/or release of neuroprotective substances to the ischemic core and the penumbra. The lower strength is less likely to cause potential side effects, such as aneurysm, that might occur if the system maintained the higher level of stimulation of the first stage. Typically, post-acute strength 634 is equal to between about 20% and 70% of minimum BBB-opening strength 610, such as between about 40% and 60%. Post-acute stage 632 typically begins at the conclusion of acute stage 630, and ends at about 16 to 30 hours after the time of the event, such as about 24 hours after the event.

The following table shows exemplary parameter ranges for some of the stimulation strengths and treatment protocols described hereinabove.

TABLE 1 Pulse No. of Cycle Signal width Cycles on/off time Indication amplitude Hz (μsec) per hour (sec) Acute 0.5-10 mA 10-30 100-500 1-10  60/12, treatment 4/15, Rehabilitation 0.5-10 mA 10-30 30/60 Prevention 0.5-10 mA 10-30 of recurrence Minimum 1-3.5 V 10-30 100-500 1-100 45/45, BTB 45/90, Minimum 1-4 V 10-30 90/60, 4/15, BBB 2/8 Maximum 3.5-8 V 10-50 BBB

As indicated in Table 1, for some applications system 310 provides stimulation by applying a plurality of cycles of stimulation, each cycle including an “on” period (e.g., between 2 and 90 seconds) followed by an “off” period (e.g., between 8 and 90 seconds). Such cycles are applied a certain number of times per hour, typically spaced evenly throughout the hour. For example, if the cycles are applied four times per hour, the four cycles may be applied at the beginning of the hour, 15 minutes into the hour, 30 minutes into the hour, and 45 minutes into the hour, respectively. For some applications, each stimulation is applied in sets of two or more cycles. For example, if the stimulation is applied four times per hour, a set of two cycles may be applied at the beginning of the hour, 15 minutes into the hour, 30 minutes into the hour, and 45 minutes into the hour, respectively.

For some applications, in order to apply different strengths for the different brain event protocols (acute treatment, post-acute treatment, rehabilitation, and prevention of recurrence of the event), system 310 changes the amplitude of the applied signal and/or the number of cycles per hour. Alternatively or additionally, the system changes the frequency, pulse width, duration of the “on” periods, duration of the “off” periods, ratio of duration of the “on” to the “off” periods, number of cycles per set of cycles, or at least one other parameter of the stimulation.

Nitric oxide (NO) influences infarct size after focal cerebral ischemia and also regulates neurogenesis in the adult brain. These observations suggest that therapeutic approaches to stroke that target NO signaling may provide neuroprotection and also enhance brain repair through cell replacement (see Zhang R et al. (2001) and Sun Y et al., cited hereinabove). Utilizing a rat model, Zhang Ret al. (2001) demonstrated that treatment of stroke with nitric oxide (NO) donors reduces functional neurological deficits. Zhang F et al. (cited hereinabove) demonstrated that NO donors increase CBF to the ischemic territory and reduce the tissue damage resulting from focal ischemia. The protective effect may result from an increase in CBF to the ischemic territory, probably the ischemic penumbra. NO and VIP have been found to be potent neuroprotectants in cell culture models (see the above-mentioned article by Sandgren K et al.). Khan M et al. (cited hereinabove), using S-nitrosothiols, a nitric oxide (NO) donor, demonstrated that administration of NO provided neuroprotection in a rat model of focal cerebral ischemia. Ziche M et al. (cited hereinabove) discuss the role of NO, as a factor responsible for vasodilation, in physiological and pathological angiogenesis. The inventors hypothesize that the release of NO induced by the stimulation techniques described herein may have therapeutic benefits, even if such stimulation is applied beginning several hours, or even several days, after the stroke.

In an embodiment of the present invention, stimulation during acute stage 630 and/or post-acute stage 632 is performed using a needle-like electrode, which is inserted, using a simple procedure, into a subject recently admitted to a hospital after a stroke. For example, the device described with reference to FIGS. 1-4B and/or FIGS. 17A-C of the above-mentioned U.S. patent application Ser. No. 11/349,020 (issued as U.S. Pat. No. 7,561,919) may be used for the acute and/or post-acute stages. Upon completion of one or both of these stages, and/or stabilization of the subject, the needle-like electrode is removed, and a longer-term stimulator is implanted and used for rehabilitative stage 636 and/or the preventive stage. For example, the device described with reference to FIGS. 5A-D, 12-14B, and/or 17A-C of the '020 application may be used for the rehabilitative and/or preventive stages.

Reference is made to FIG. 28, which is a graph 650 showing a rehabilitation protocol for treating stroke, in accordance with an embodiment of the present invention. In accordance with this protocol, system 310 is configured to alternatingly apply stimulation at a first, rehabilitative level of strength, and at a second BBB-opening level of strength in conjunction with administration of a drug for rehabilitation from stroke. For example, the drug may include a growth factor, such as BDNF, GDNF, or NGF. Typically, the first rehabilitative level is rehabilitation strength 620, described hereinabove with reference to FIG. 27, and the second BBB-opening level falls within BBB-opening range 608, such as maximum BBB-opening strength 612, described hereinabove with reference to FIG. 27. System 310 is typically configured to apply the rehabilitative stimulation intermittently, such as during one session per day, having a duration of between about 1 and about 6 hours, such as between about 2 and about 4 hours day, e.g., about 3 hours. Alternatively, the rehabilitative stimulation is applied less frequently than every day, such as once every other day, or more frequently than once per day, such as during two sessions per day.

System 310 is typically configured to apply the BBB-opening stimulation intermittently, such as for between about 0.5 and about 1 hour per day, or for between about 3 and about 6 hours per day, e.g., about 4 hours per day. Alternatively, the BBB-opening stimulation is applied less frequently than every day, such as once every other day, or more frequently than once per day, such as twice per day, or 24 times per day. The drug administered in conjunction with applying the BBB-opening stimulation is typically administered systematically, before and/or during application of the BBB-opening stimulation. For some applications, the rehabilitative stimulation is applied immediately before or after the BBB-opening stimulation (as shown in FIG. 28), while for other applications the rehabilitative and BBB-opening stimulations are applied non-contiguously (not shown in FIG. 28).

Reference is made to FIG. 29, which is a graph showing changes in CBF vs. baseline using three different SPG stimulation protocols, measured in accordance with an embodiment of the present invention. 16 naïve rats were anesthetized with a ketamine-xylazine combination, and a plastic holder was affixed to the skull for CBF measurement. A bipolar electrode was brought into contact with the SPG and connected to a controller. The SPG was stimulated for five minutes beginning after CBF stabilization, using the following signal parameters: 3.5 volts, 10 Hz, and a 500 μsec pulse width. The rats were divided into four groups, one of which served as a control, and the other three received stimulation having different duty cycles: 4 seconds on/15 seconds off, 60 seconds on/12 seconds off, and 90 second on/60 second off. As can be seen in FIG. 29 and in Table 2 below, CBF significantly increased in two of the stimulation groups (4/15 and 60/12) vs. CBF baseline. The maximum increase in CBF vs. baseline (193%) was observed in the 60/12 stimulation group after two minutes of SPG stimulation. CBF in this group remained elevated even 10-15 minutes after termination of SPG stimulation. The minimum increase in CBF vs. baseline (141%) was observed in the 90/60 stimulation group. It is clear from these results that SPG stimulation at the described parameters significantly increases CBF, and that such increase was stable at 10 minutes following SPG stimulation.

TABLE 2 CBF at 2 minutes [% change Group from baseline]  4/15 (n = 5) 157 60/12 (n = 6) 193 90/60 (n = 5) 141

Reference is made to FIGS. 30-35C, which are graphs showing in vivo experimental results, measured in accordance with respective embodiments of the present invention. These animal experiments were performed to test the efficacy of the SPG stimulation techniques described hereinabove for treating stroke. The experiments described with reference to FIGS. 30-35C used a rat middle cerebral artery occlusion (MCAO) model of stroke. As described in detail hereinbelow, these experiments demonstrated that:

-   -   SPG stimulation starting three hours following MCAO occlusion         significantly improved cerebral blood flow (CBF), decreased         infract size, and improved neuromuscular function;     -   SPU stimulation reduced mortality;     -   SPG stimulation for one or three hours per day for three days,         beginning 24 hours after MCAO, improved neuromuscular functions         for nine days following the insult; and     -   SPG stimulation for six hours per day for six days, beginning 24         hours after MCAO improved neuromuscular function at 13 and 28         days following occlusion.

Reference is made to FIG. 30, which is a graph showing the effect of SPG stimulation beginning three hours after permanent MCAO (pCMAO) in male rats, measured in accordance with an embodiment of the present invention. The graph shows changes in CBF vs. baseline, in an experimental group (n=12) and in a control group (n=12). The Sprague Dawley® (SD) rats were anesthetized with a ketamine-xylazine combination (85 mg/kg and 5 mg/kg respectively), and pMCAO was performed as follows. The right common carotid artery (CCA) was exposed through a midline neck incision and carefully dissected free from surrounding nerves and fascia, from its bifurcation to the base of the skull. The occipital artery branches of the external carotid artery (ECA) were then isolated, and these branches were dissected and coagulated. The ECA was dissected further distally and coagulated together with the terminal lingual and maxillary artery branches, which was then divided. The internal carotid artery (ICA) was isolated and carefully separated from the adjacent vagus nerve, and the pterygopalatine artery was ligated close to its origin with a 5-0 nylon suture. A 4-0 silk suture was tied loosely around the mobilized ECA stump, and a 4 cm length of 4-0 monofilament nylon suture (the tip of the suture was blunted by using a flame, and the suture was coated with silicone, prior to insertion) was inserted through the proximal ECA into the ICA, and from there into the circle of Willis, effectively occluding the MCA. The surgical wound was closed and the rats were returned to their cages to recover from anesthesia. These techniques for performing pMCAO are similar to those described in the above-mentioned article by Schmid-Elsaesser R et al.

SPG stimulation was initiated at three hours following pMCAO. The stimulation regime included a duty cycle of 60 seconds on/12 seconds off, at 2 mA and 10 Hz, with a 500 μsec pulse width. The stimulation was applied for five minutes every 30 minutes, for a period of 10 hours. As can be seen in FIG. 30, SPG stimulation markedly and significantly increased CBF levels in rats after pMCAO. The greatest increase was observed at 6 hours following MCAO.

FIGS. 31 and 32 are graphs showing results of an in vivo experiment assessing the effect of SPG stimulation performed three hours following stroke, measured in accordance with an embodiment of the present invention. A rat pMCAO model of stroke was used to evaluate the neuroprotective benefits of SPG stimulation following stroke using techniques described herein. A three-hour delay prior to applying stimulation was chosen to simulate the relatively late-stage intervention common in clinical settings. The results of this experiment demonstrate that SPG stimulation provided significant neuroprotection. SPG stimulation reduced mortality, significantly improved neuromuscular function, and increased CBF.

32 SD rats were divided into an experimental group (n=15), and a control group (n=17). pMCAO was performed using the techniques described hereinabove. A bipolar electrode was brought into contact with the SPG ipsilateral to the pMCAO, and connected to a controller.

Three hours after pMCAO and prior to commencement of stimulation, all of the rats were subjected to the first of three neuroscoring (behavioral) tests. Additional neuroscoring was performed at 24 and 48 hours post-pMCAO. SPG stimulation was initiated at three hours following pMCAO occlusion. The stimulation regime included a duty cycle of 60 seconds on/12 seconds off, at 2 mA and 10 Hz, with a 500 μsec pulse width. The stimulation was performed for five minutes every 30 minutes, for a period of 10 hours. Forty-eight hours following pMCAO, the rats were sacrificed, and their brains were removed for triphenyltetrazolium chloride (TTC) staining. Infarct volume was quantified at each coronal level in the area of the contralateral hemisphere and the ipsilateral spared hemisphere. The volume of the total infarct was measured. The infarct volume was quantified by computerized morphometric analysis using an imaging program.

As can be seen in FIG. 31 and in Table 3 below, SPG stimulation increased CBF levels in the experimental group vs. the control group. SPG stimulation also decreased the sub-cortical and cortical infarct volume in the experimental group vs. the control group, as measured at forty-eight hours following pMCAO, as can be seen in FIG. 32, which shows the infarct volume as a percentage of the total volume of both hemispheres, and in Table 3. Mortality was lower in the experimental group than in the control group, and neuroscore was higher in the experimental group than in the control group, as is shown in Table 3.

TABLE 3 CBF (at 6 hours after Infarct MCAO) volume (at Neuroscore [ml/min/ Mortality 48 hours) (at 24 hours) Group 100 g] [%] [%] [arbitrary units] Control 99.3 47.1 38.3 3.3 Experimental 141.7 26.7 25.3 3.6

FIGS. 33A-C are graphs showing the results of in vivo experiments assessing the effect of SPG stimulation performed three hours following stroke, measured in accordance with respective embodiments of the present invention. A rat pMCAO model of stroke was used to evaluate the neuroprotective benefits of SPG stimulation following stroke using techniques described herein. Other than as described below, these experiments were conducted in the same manner as those described hereinabove with respect to FIGS. 31 and 32 and Table 3. 24 SD rats were divided into an experimental group (n=17), and a control group (n=12).

As can be seen in FIG. 33A, SPG stimulation increased CBF levels in the experimental group vs. the control group. SPG stimulation also decreased the sub-cortical and cortical infarct volume in the experimental group vs. the control group, as measured at forty-eight hours following pMCAO, as can be seen in FIG. 33B, which shows the infarct volume as a percentage of the total volume of both hemispheres. Neuroscore was slightly lower in the experimental group than in the control group at 3 hours after pMCAO, but was significantly (P<0.05) higher in the experimental group at 24 hours after pMCAO, as shown in FIG. 33C (neuroscore was assessed on a scale of 0 to 12, with 12 representing the best performance).

Reference is made to FIG. 34, which is a graph showing results of an in vivo experiment assessing the effect of rehabilitative SPG stimulation, measured in accordance with an embodiment of the present invention. A rat MCAO (middle cerebral artery occlusion) model of stroke was used to evaluate the neuromuscular benefits of rehabilitative SPG stimulation using the techniques described herein. 47 rats were divided into three groups: a control group (n=18); a first experimental group (n=16), which received one hour of SPG stimulation per day; and a second experimental group (n=13), which received three hours of SPG stimulation per day. pMCAO was performed using the techniques described hereinabove with reference to FIG. 30. A bipolar electrode was brought into contact with the SPG ipsilateral to the pMCAO, and connected to a controller. SPG stimulation was initiated at 24 hours after pMCAO, in order to demonstrate the potential rehabilitative effects of such stimulation, rather than the acute benefits. The first and second experimental groups each received SPG stimulation at 24 hours, 48 hours, and 72 hours after pMCAO. The stimulation regime included a duty cycle of 60 seconds on/12 seconds off, at 2 mA and 10 Hz, with a 500 μsec pulse width. As mentioned above, the stimulation was performed for one hour per day in the first experimental group, and three hours per day in the second experimental group.

At 24, 48, 72, 96, and 216 hours after pMCAO, the rats were tested using a modified neuroscore battery, which assessed the severity of damage on a scale of 0 to 10, with 10 representing the greatest deficit. As can be seen in FIG. 34, the rats in both the first and second experimental groups achieved better (lower) neuroscores than the control group at all tested time periods after pMCAO, with statistical significance achieved for the second (3 hour stimulation) experimental group at nine days after pMCAO.

Reference is made to FIGS. 35A-C, which are graphs showing results of an in vivo experiment assessing the effect of rehabilitative SPG stimulation, measured in accordance with an embodiment of the present invention. A rat MCAO model of stroke was used to evaluate the benefits, including neuromuscular benefits, of rehabilitative SPG stimulation using the techniques described herein. 29 rats were divided into an experimental group (n=16) and a control group (n=13). Transient MCAO (tMCAO) was performed as follows. The right common carotid artery (CCA) was exposed through a midline neck incision and carefully dissected free from surrounding nerves and fascia, from its bifurcation to the base of the skull. The occipital artery branches of the external carotid artery (ECA) were isolated, and these branches were dissected and coagulated. The ECA was further dissected distally and coagulated together with the terminal lingual and maxillary artery branches, which were divided. The internal carotid artery (ICA) was isolated and carefully separated from the adjacent vagus nerve, and the pterygopalatine artery was ligated close to its origin with a 5-0 nylon suture. A 4-0 silk suture was tied loosely around the mobilized ECA stump, and a 4 cm length of 4-0 monofilament nylon suture (the tip of the suture was blunted using a flame, and the suture was coated with silicone, prior to insertion) was inserted through the proximal ECA into the ICA, and from there into the circle of Willis, effectively occluding the MCA. The suture was placed for three hours and thereafter removed. The surgical wound was closed, and the animals were returned to their cages to recover from the procedure. These techniques for performing tMCAO are similar to those described in the above-mentioned article by Schmid-Elsaesser R et al. On the day of the tMCAO procedure, a bipolar electrode was implanted in contact with the SPG ipsilateral to the tMCAO, and connected to a controller.

At 24 hours after tMCAO, and prior to commencement of the first stimulation, neurological evaluation was performed on the rats using the modified Neurological Severity Score (mNSS) scale. Only animals with an overall score of at least 12 were included in the experiment. The rats in the experimental group received SPG stimulation for 6 hours per day for 6 days, beginning 24 hours after tMCAO. The stimulation regime included a duty cycle of 60 seconds on/12 seconds off, at 2 mA and 10 Hz, with a 500 μsec pulse width. Neuroscores were assessed at days 6, 13, and 28 after tMCAO, using behavioral tests aimed at studying neuromuscular function. FIGS. 35A and 35B show results obtained at days 13 and 28, respectively (the mNSS scale ranges from 0 to 12, with best performance indicated by a 12). A significant improvement in neuromuscular function can be seen at both days 13 and 28. FIG. 35C shows the results of a stepping test for the left and right paws. A significant improvement in motor function in the experimental group compared with the control group can be seen for the contralateral (left) paw.

Reference is made to FIGS. 36A-H, which are graphs showing results of an in vivo experiment assessing the effect of long-term rehabilitative SPG stimulation, measured in accordance with an embodiment of the present invention. A rat tMCAO model of stroke was used to evaluate the benefits, including neuromuscular, motility, cognitive, somatosensory, somatomotor, infarct volume benefits, of rehabilitative SPG stimulation using the techniques described herein. The stimulation was applied for seven consecutive days beginning at 24 hours after reperfusion in the tMCAO model.

94 male Sprague Dawley (SD) rats were divided into six groups, as shown in Table 4:

TABLE 4 Hours of stimulation Group No. of rats per day 1 - Control 18 N/A 2 - Sham 10 N/A 3 17 1 4 16 3 5 17 6 6 16 10

Prior to performance of any surgical procedure on the rats, the rats were trained using a series of behavior tests. Five parameter categories were evaluated using one or more tests, as follows:

-   -   Neuromuscular function—rotarod motor test, mNSS test, beam         walking and balance test, stepping test, and staircase skilled         reaching test;     -   Motility—open field test;     -   Learning memory (cognitive)—water maze test;     -   Somatosensory sensation—adhesive removal test; and     -   Somatomotor sensation—corner turn test.

Transient MCAO (tMCAO) was performed on the right hemisphere of all of rats except those of the sham group, using the techniques described hereinabove with reference to FIGS. 35A-C. Three hours after the occlusion, reperfusion was allowed in all groups. On the day of tMCAO, the rats were anesthetized, and a bipolar electrode was implanted in contact with the SPG ipsilateral to the pMCAO (i.e., the right SPG), and connected to a controller. At 24 hours post-tMCAO (just prior to stimulation), the rats were subjected to neuroscoring using the mNSS scale, which has a score range of 0-18, where 0 represents normal and 18 represents maximum neurological defect. Rats scoring less than or equal to 9 were excluded from the experiment.

SPG stimulation was applied for seven consecutive days beginning at 24 hours post-tMCAO, using the following regime: a duty cycle of 60 seconds on/12 seconds off, with two cycles every 15 minutes, at 2 mA and 10 Hz, with a 500 μsec pulse width. The stimulation was applied for fifteen minutes every 60 minutes. The number of hours of stimulation per day was as shown in Table 4 above.

In order to assess rehabilitation, on days 8, 14, and 35 post-tMCAO, (with limited exceptions for specific tests), the rats were subjected to the same pre-procedure behavior tests used in the training, as described hereinabove. One day after the last behavior testing, the rats were sacrificed and perfused. Their brains were harvested, infarct volume was measured, and neurons were counted.

The results of the experiment included the following:

-   -   Mortality in the SPG-stimulated groups was lower than in the         non-stimulated control group.     -   SPG stimulation generally improved neuromuscular functions         (rotarod, mNSS, beam walk and balance, stepping and staircase         tests) in comparison to the non-stimulated control group.     -   SPG stimulation improved cognitive capabilities (water maze         test) in comparison to the non-stimulated control group.     -   There was a trend towards increased motility (open field test)         in the SPG-stimulated groups.     -   Somatosensory sensations were enhanced in the SPG-stimulated         groups in comparison to the non-stimulated control group.     -   Somatomotor competence was superior in the SPG-stimulated groups         than in the non-stimulated control groups.     -   SPG stimulation resulted in higher neurons counts in cortical         layer V of the ipsilateral stimulated side in comparison to the         non-stimulated control group.

In summary, in the present experiment, SPG stimulation initiated 24 hours after tMCAO had advantageous results for all five parameter groups evaluated. In addition, SPG stimulation increased the number of neurons in all regions counted.

FIG. 36A is a graph showing neuroscores (mNSS test) of all six groups, measured at 24 hours, 8 days, 14 days, and 35 days after tMCAO, measured in accordance with an embodiment of the present invention. As can be seen in the graph, mNSS scores of the SPG-stimulated rats decreased in a time-dependent manner post-tMCAO, indicating the occurrence of an active restorative, rehabilitative process. SPG stimulation markedly and significantly (p<0.05) improved neurological function measured at days 8, 14, and 35 in all SPG-stimulated groups.

FIG. 36B is a graph showing the results of the stepping test performed on the left foreleg in all six groups, measured pre-tMCAO and at 8 days, 14 days, and 35 days after tMCAO, measured in accordance with an embodiment of the present invention. As can be seen in the graph, there was a significant (p<0.05) increase in left (impaired) foreleg stepping in all SPG-stimulated rats in comparison to the non-stimulated control group (with the exception of the 10-hour stimulated group at day 35). Maximum improvement was evident in the 3- and 6-hour stimulation groups at days 14 and 35, respectively.

FIGS. 36C-F are graphs showing the results of the Morris water maze (WM) task, measured in accordance with an embodiment of the present invention. The Morris WM task is a standard test of learning in which the animal repeatedly searches for a rest platform hidden beneath the surface in a pool. The test is especially sensitive to hippocampal and cortical damage, and reflects attention, memory, and learning strategy. The Morris WM task was performed on days 14 and 35 following tMCAO.

FIG. 36C is a graph showing the latency to the first occurrence in the Old Zone (as described below) in first and second trials at 14 days after tMCAO, measured in accordance with an embodiment of the present invention. This parameter assesses the rats' functional memory. The rest platform was moved from the Old Zone (its position during training) to the New Zone (its position during testing), and the rats were expected to seek the Old Zone. The first trial showed that the SPG-stimulated rats (3-, 6-, and 10-hour stimulation) returned to the Old Zone significantly (p<0.05) more quickly than the non-stimulated rats in the control group. The second trial showed, although non-significantly, that the SPG-stimulated rats returned to the Old Zone faster than the non-stimulated controls, even though introduced to the New Zone rest platform in the first trial. The second trial thus confirmed that the SPG-stimulated rats showed enhanced remnants of functional memory.

FIG. 36D is a graph showing time spent in the Old Zone at day 14 after tMCAO, measured in accordance with an embodiment of the present invention. This parameter also assesses the rats' functional memory. As can be seen in the graph, the 3-, 6-, and 10-hour SPG-stimulated groups spent significantly (p<0.05) more time seeking the rest platform in the Old Zone in comparison to the non-stimulated control group.

FIG. 36E is a graph showing the latency to the first occurrence in the New Zone in first and second trials at day 35 after tMCAO, measured in accordance with an embodiment of the present invention. This parameter also assessed the rats' functional memory. In the first trial, the 3-, 6-, and 10-hour SPG-stimulated groups demonstrated superior, although non-significant, results in finding the New Zone, compared with the non-stimulated control group. In the second trial, all of the SPG-stimulated groups achieved better results than the non-stimulated control group. These results were significant (p<0.05) only in the 3-hour stimulated group.

FIG. 36F is a graph showing the distance moved to find the rest platform in the New Zone in first and second trials at day 35 after tMCAO, measured in accordance with an embodiment of the present invention. This parameter assessed the rats' long-term learning capability. In both trials the SPG-stimulated rats demonstrated better performance than the control group. These results were significant (p<0.05) only in the 3-hour stimulated group during the first trial.

The staircase test (results not shown) was performed to assess the rehabilitation of foreleg fine motorics. At day 14 after tMCAO the SPG-stimulated groups demonstrated better performance in the left impaired foreleg than the control group (1-, 3-, and 6-hour stimulation, significant (p<0.05) in the 3- and 6-hour stimulated rats only). At day 35 after tMCAO the SPG-stimulated groups demonstrated better performance in the left impaired foreleg, significant (p<0.05) in the 3-hour stimulated rats only.

The rotarod test (results not shown) was performed to assess the rats' ability to remain on a rotating rod. It requires a high degree of sensorimotor coordination and is sensitive to damage in the basal ganglia and the cerebellum. The only significant (p<0.05) results were in the 3-hour stimulated rats on the 35 day assessment, which remained on the rotarod significantly longer than the control group.

FIG. 36G is a graph showing the time required for the rats to remove an adhesive patch from the left foreleg, measured in accordance with an embodiment of the present invention. This test assessed both cutaneous sensitivity and sensor motor integration, and is analogous to human neurological tests used clinically in stroke patients. In the left impaired foreleg, the SPG-stimulated rats showed better results than the non-stimulated controls at all assessment days (8, 14, and 35 days). These results were significant (p<0.05) at all three assessment days in the 3- and 6-hour stimulated groups only.

The corner test (results not shown) was performed to evaluate the rats' tendency to favor a turn in the direction of the ipsilateral side of the tMCAO (i.e., the right side in the experiment). On all three assessment days (8, 14, and 35 days), all SPG-stimulated groups showed a decrease in right side turns in comparison to the non-stimulated control group. This decrease was significant (p<0.05) only on day 35 in the 1- and 6-hour stimulated rats.

The beam walk test (results not shown) was performed to evaluate sensor motor integration, specifically hind limb function. In general, all SPG-stimulated groups showed improved results in comparison to the non-stimulated control group. These results were significant (p<0.05) only on day 35 only in the 3-hour stimulated group.

The beam balance test (results not shown) was performed to assess gross vestibulomotor function, by requiring the rats to balance steadily on a narrow beam. This test is sensitive to motor cortical insults. On all assessment days (days 8, 14, and 35), all of the SPG-stimulated groups (except the 1-hour stimulated group on day 8) performed better than the non-stimulated control group. These results were significant (p<0.05) only on day 14 in the 3-hour stimulated group.

The open field test (results not shown) was performed to assess the following four parameters indicative of hippocampal and basal ganglia damage, as well as hind limb dysfunction:

-   -   Total distance moved, which decreases in cerebrally-insulted         animals. All of the SPG-stimulated groups achieved enhanced         movement compared to the control group on day 14 after tMCAO.         These results were significant (p<0.05) only in the 3- and         6-hour stimulated groups.     -   Velocity, which is diminished in cerebrally-insulted animals.         All of the SPG-stimulated groups achieved enhanced velocity         compared to the control group on day 14 after tMCAO. These         results were significant (p<0.05) only in the 3- and 6-hour         stimulated groups.     -   Latency of first occurrence in center zone. All of         SPG-stimulated groups (except the 10-hour stimulated group on         day 14) showed quicker entry into the center zone in comparison         to the non-stimulated control group. These results were         significant (p<0.05) only on day 35 in the 1- and 3-hour         stimulated groups.     -   Total distance moved in center zone. On day 14, the 3- and         10-hour stimulated groups achieved significantly (p<0.05)         greater distance moved than the control group.

FIG. 36H is a graph showing the number of neurons in cortical layer V and measured in accordance with an embodiment of the present invention. Neuron counting was performed in cortical layers V and II-III in the non-stimulated control group and in the 3- and 6-hour SPG-stimulated groups. The number of neurons in cortical layer V was significantly (p<0.05) greater in both of these SPG-stimulated groups compared to the non-stimulated group. In cortical layers II-III there was no significant difference between the stimulated and non-stimulated groups.

There were no significant differences in body weigh between the SPG-stimulated groups and the non-stimulated control group.

The inventors are currently performing an in vivo experiment to compare the application of SPG stimulation for 28 days with the application of SPG stimulation for 7 days, as applied in the experiment described hereinabove with reference to FIGS. 36A-H. The experimental protocol is similar to that of this above-mentioned experiment. Preliminary results of this current experiment indicate that application of SPG stimulation for the longer 28-day period has greater therapeutic benefits than application of the stimulation for 7 days:

Table 5 shows the results of an in vivo experiment performed to test whether long-term stimulation of the SPG using a protocol appropriate for treating stroke damages the BBB, measured in accordance with an embodiment of the present invention. 31 rats (males, Wistar™, 12 weeks, average body weight 300 g) were divided to three groups: an SPG stimulation group (n=13), which had an SPG stimulator implanted; a first control group (n-12), which was not stimulated, and had a sham operation; and a second control group (n=6), which had a sham operation, and was exposed to an RF electromagnetic field for 24 hours. The SPG stimulation group received 24 hours of continuous SPG stimulation with a stimulation regime that included a duty cycle of 90 seconds on/60 seconds off, at 5 V and 10 Hz, with a 1 millisecond pulse width. Upon completion of stimulation, a marker (Evans blue (EB) (2%)), which normally does not cross the BBB, was intravenously (2 ml) injected into the rats. 48 hours following the EB administration, 500 ml of cold saline was used for perfusion of blood and EB from the rats' circulation. Thereafter, the rats' brains were removed, the left and right hemispheres were homogenized, and brain EB concentration was determined using an Elisa Reader at 630 nm. As can be seen in Table 5, stimulation for 24 hours did not cause leakage of EB into the brain, indicating that the stimulation did not cause damage to the BBB.

TABLE 5 Right Left Group Hemisphere Hemisphere First Control (non-stimulated) (n = 12) 0.04 ± 0.03 0.02 ± 0.02 Second Control (RF-exposed) (n = 6) 0.03 ± 0.02 0.04 ± 0.02 Experimental (stimulated) (n = 13) 0.03 ± 0.02 0.02 ± 0.02

The inventors performed in vivo experiments in rats to assess the safety of SPG stimulation techniques described herein. These experiments showed that stimulation did not break down the BBB, and that stimulation was found to be safe in a battery of motor and cognitive tests, which were in general agreement with histological analysis.

In an embodiment of the present invention, a calibration procedure is performed, in which a test molecule is injected into the systemic blood circulation of the subject, and a threshold stimulation strength is determined by stimulating at least one MTS, and gradually increasing the stimulation strength until the BBB is opened (e.g., as determined using a radioactive scanning technique). System 310 applies therapeutic stimulation to an MTS using a strength equal to a certain percentage of the threshold strength, typically less than 100%.

Reference is made to FIG. 37, which is a graph 660 showing a protocol for treating a brain tumor, in accordance with an embodiment of the present invention. In accordance with this protocol, a method for treating a brain tumor comprises: (a) during a first period of time 670, applying excitatory electrical stimulation to at least one MTS at a first, relatively low strength 652, in conjunction with administration of a chemotherapeutic drug at a first, relatively high dosage 674; and (b) during a second period of time 676, applying the stimulation at a second strength 678 greater than first strength 652, in conjunction with administration of the drug at a second dosage 680 lower than first dosage 674. Alternatively, the drug is administered only at the first dosage, and the stimulation is applied at second strength 678 after the level of the drug in the systemic circulation has dropped because of ordinary metabolic drug clearance from the circulation. For some applications, the protocol shown for second period 676 is applied after first period 670 (as shown). For other applications, the protocol shown for the second period is applied before the protocol shown for the first period. Alternatively, two different chemotherapeutic drugs are applied during the first and second periods, respectively, not necessarily at different dosages.

The blood-tumor barrier (BTB) of the core and tissue near the core of a growing brain tumor is generally damaged by the natural progression of the tumor. During first period 670, stimulation applied at first strength 672 is thus sufficient to further open the BTB of the core and tissue near the core, but not sufficient to open the BBB of the periphery of the tumor or of other cells in the brain. In other words, first strength 672 is between a BTB opening strength 673 and maximum BBB-opening strength 612. As a result, high dosage 674 of the chemotherapeutic drug is targeted at the core and tissue near the core of the tumor, since the drug is substantially unable to enter other brain cells, because of their intact BBB and the large molecular size of the drug. During second period 676, stimulation at higher second strength 678 opens the BBB of other brain cells, including tumor cells in the periphery of the core and/or other areas of the brain. For some applications, second strength 678 is greater than or equal to maximum BBB-opening strength 612, as shown in FIG. 37. Alternatively or additionally, second strength 678 is sufficient to induce a significant increase in the permeability of the BBB. Second dosage 680 is low enough not to substantially damage non-tumor cells. For some applications, the dosage is set to the highest level that does not cause systemic and/or brain toxicity; this level is higher during first period 670 than during second period 676, because of the lower level of MTS stimulation during the first period than during the second period. For some applications, only the protocol for the first period is applied, when this is deemed sufficient to facilitate delivery of the drug to the core and tissue near the core while generally avoiding facilitating delivery of the drug into other brain cells. For some applications, in order to determine the appropriate parameters for increasing the permeability of the BTB and/or BBB for this embodiment, a calibration procedure is performed in which the uptake of a substance across the BTB and/or BBB is measured at a plurality of stimulation parameters (e.g., using a radioactive isotope or other marker known in the art).

In an embodiment of the present invention, bipolar stimulation is applied, in which a first electrode is applied to a first MTS, and a second electrode is applied to a second MTS.

In an embodiment of the present invention, an SPG of the subject is indirectly activated by stimulating a branch of cranial nerve V of the subject, including, for example, afferent fibers of cranial nerve V, either electrically, magnetically, or electromagnetically. A reflex response to such stimulation leads to activation of the SPG. Typically, the stimulation is performed while the subject is under general anesthesia or sedation. For some applications, cranial nerve V is stimulated by non-invasively attaching electrodes to the surface of the face of the subject, typically using techniques commonly used for transcutaneous electrical nerve stimulation (TENS).

In an embodiment of the present invention, an SPG of the subject is indirectly activated by stimulating afferent fibers of the trigeminal nerve (cranial nerve V) of the subject, either electrically, magnetically, or electromagnetically. A reflex response to such stimulation leads to activation of the SPG. (For example, the maxillary branch of the trigeminal nerve directly contacts the SPG.) Typically, but not necessarily, such stimulation is performed while the subject is under general anesthesia or sedation. For some applications, cranial nerve V is stimulated by non-invasively attaching electrodes to the surface of the face of the subject, typically using techniques commonly used for transcutaneous electrical nerve stimulation (TENS). For example, TENS may be applied to a cheek or a tip of a nose of a subject. In an embodiment of the present invention, an oral appliance is provided that is configured to be brought into contact with a mucous membrane of a palate of an oral cavity of a subject. The appliance comprises one or more electrodes, which are driven to apply transmucosal electrical stimulation to nerve fibers within or immediately above the mucous membrane, which fibers directly innervate an SPG of the subject. Typically, but not necessarily, such stimulation is performed while the subject is under general anesthesia or sedation. Such transmucosal stimulation may require less current than the transcutaneous stimulation described hereinabove.

In some embodiments of the present invention, techniques described herein are practiced in combination with techniques described in one or more of the references cited in the Background of the Invention section hereinabove and/or in combination with techniques described in one or more of the patent applications cited hereinabove.

The scope of the present invention includes embodiments described in the following patent applications, which are assigned to the assignee of the present patent application and are incorporated herein by reference. In an embodiment of the present invention, techniques and apparatus described in one or more of the following applications are combined with techniques and apparatus described herein:

-   -   U.S. Provisional Patent Application 60/203,172, filed May 8,         2000, entitled, “Method and apparatus for stimulating the         sphenopalatine ganglion to modify properties of the BBB and         cerebral blood flow”     -   U.S. patent application Ser. No. 10/258,714, filed Oct. 25,         2002, which issued as U.S. Pat. No. 7,120,489, entitled, “Method         and apparatus for stimulating the sphenopalatine ganglion to         modify properties of the BBB and cerebral blood flow,” or the         above-referenced PCT Publication WO 01/85094     -   U.S. Provisional Patent Application 60/364,451, filed Mar. 15,         2002, entitled, “Applications of stimulating the sphenopalatine         ganglion (SPG)”     -   U.S. Provisional Patent Application 60/368,657, filed Mar. 28,         2002, entitled, “SPG Stimulation”     -   U.S. Provisional Patent Application 60/376,048, filed Apr. 25,         2002, entitled, “Methods and apparatus for modifying properties         of the BBB and cerebral circulation by using the neuroexcitatory         and/or neuroinhibitory effects of odorants on nerves in the         head”     -   U.S. Provisional Patent Application 60/388,931, filed Jun. 14,         2002, entitled “Methods and systems for management of         Alzheimer's disease,” PCT Patent Application PCT/IL03/000508,         filed Jun. 13, 2003, claiming priority therefrom, and which         published as PCT Publication WO 03/105658, and U.S. patent         application Ser. No. 10/518,322, filed Dec. 14, 2004 in the         national stage thereof, which issued as U.S. Pat. No. 7,640,062     -   U.S. Provisional Patent Application 60/400,167, filed Jul. 31,         2002, entitled, “Delivering compounds to the brain by modifying         properties of the BBB and cerebral circulation”     -   U.S. Provisional Patent Application 60/426,180, filed Nov. 14,         2002, entitled, “Surgical tools and techniques for         sphenopalatine ganglion stimulation,” PCT Patent Application         PCT/1L03/000966, filed Nov. 13, 2003, which claims priority         therefrom, and which published as PCT Publication WO 04/043218,         and U.S. patent application Ser. No. 10/535,024, filed May 11,         2005 in the national stage thereof, which issued as U.S. Pat.         No. 7,636,597     -   U.S. Provisional Patent Application 60/426,182, filed Nov. 14,         2002, and corresponding PCT Patent Application PCT/IL03/000967,         which claims priority therefrom, filed Nov. 13, 2003, which         published as PCT Publication WO 04/044947, entitled,         “Stimulation circuitry and control of electronic medical         device,” and a US patent application filed May 11, 2005 in the         national stage thereof     -   U.S. patent application Ser. No. 10/294,310, filed Nov. 14,         2002, which issued as U.S. Pat. No. 7,146,209, entitled, “SPG         stimulation for treating eye pathologies,” and PCT Patent         Application PCT/IL03/000965, filed Nov. 13, 2003, claiming         priority therefrom, which published as PCT Publication WO         04/043217     -   PCT Patent Application PCT/IL03/000631, filed Jul. 31, 2003,         which published as PCT Publication WO 04/010923, entitled,         “Delivering compounds to the brain by modifying properties of         the BBB and cerebral circulation,” and U.S. patent application         Ser. No. 10/522,615, filed Jan. 31, 2005 in the national stage         thereof     -   U.S. Pat. No. 6,853,858 to Shalev     -   U.S. patent application Ser. No. 10/783,113, filed Feb. 20,         2004, which issued as U.S. Pat. No. 7,117,033, entitled,         “Stimulation for acute conditions”     -   U.S. Provisional Patent Application 60/426,181, filed Nov. 14,         2002, entitled, “Stimulation for treating ear pathologies,” PCT         Patent Application PCT/IL03/000963, filed Nov. 13, 2003, which         claims priority therefrom, and which published as PCT         Publication WO 04/045242, and U.S. patent application Ser. No.         10/535,025, filed May 11, 2005 in the national stage thereof     -   U.S. Provisional Patent Application 60/448,807, filed Feb. 20,         2003, entitled, “Stimulation for treating autoimmune-related         disorders of the CNS”     -   U.S. Provisional Patent Application 60/461,232 to Gross et al.,         filed Apr. 8, 2003, entitled, “Treating abnormal conditions of         the mind and body by modifying properties of the blood-brain         barrier and cephalic blood flow”     -   PCT Patent Application PCT/IL03/00338 to Shalev, filed Apr. 25,         2003, which published as PCT Publication WO 03/090599, entitled,         “Methods and apparatus for modifying properties of the BBB and         cerebral circulation by using the neuroexcitatory and/or         neuroinhibitory effects of odorants on nerves in the head,” and         U.S. patent application Ser. No. 10/512,780, filed Oct. 25, 2004         in the national stage thereof, which published as US Patent         Application 2005/0266099     -   U.S. Provisional Patent Application 60/506,165, filed Sep. 26,         2003, entitled, “Diagnostic applications of stimulation”     -   U.S. patent application Ser. No. 10/678,730, filed Oct. 2, 2003,         which published as US Patent Application Publication         2005/0074506, entitled, “Targeted release of nitric oxide in the         brain circulation for opening the BBB,” and PCT Patent         Application PCT/IL04/000911, filed Oct. 3, 2004, claiming         priority therefrom, which published as PCT Publication WO         05/030118     -   PCT Patent Application PCT/IL04/000897, filed Sep. 26, 2004,         entitled, “Stimulation for treating and diagnosing conditions,”         which published as PCT Publication WO 05/030025     -   U.S. Provisional Patent Application 60/604,037, filed Aug. 23,         2004, entitled, “Concurrent bilateral SPG modulation”     -   PCT Patent Application PCT/IL05/000912, filed Aug. 23, 2005,         entitled, “Concurrent bilateral SPG modulation,” which published         as PCT Publication WO 06/021957     -   U.S. patent application Ser. No. 10/952,536, filed Sep. 27,         2004, entitled, “Stimulation for treating and diagnosing         conditions,” which published as US Patent Application         Publication 2005/0159790 (now abandoned)     -   U.S. Provisional Patent Application 60/709,734, filed Aug. 19,         2005, entitled, “Stimulation for treating brain events and other         conditions”     -   U.S. patent application Ser. No. 11/349,020, filed Feb. 7, 2006,         which issued as U.S. Pat. No. 7,561,919, entitled, “SPG         stimulation via the greater palatine canal”     -   U.S. Pat. No. 7,561,919 to Shalev et al.     -   U.S. Pat. No. 8,055,347 to Lamensdorf et al.

In an embodiment of the present invention, system 20 and/or 120 comprises circuitry described in one or more of the above-mentioned applications.

In an embodiment of the present invention, electrical stimulation system 310 comprises circuitry described in one or more of the above-mentioned applications.

In an embodiment of the present invention, an MTS is stimulated using the magnetic stimulation apparatus and methods described in the above-mentioned U.S. patent application Ser. No. 10/783,113.

As used in the present application and in the claims, the BBB comprises the tight junctions opposing the passage of most ions and large molecular weight compounds between the blood and brain tissue. As used in the present application and in the claims, the BTB comprises a barrier opposing the passage of many ions and large molecular weight compounds between the blood and tissue of a brain tumor.

It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof that are not in the prior art, which would occur to persons skilled in the art upon reading the foregoing description. For example, elements which are shown in a figure to be housed within one integral unit may, for some applications, be disposed in a plurality of distinct units. Similarly, apparatus for communication and power transmission which are shown to be coupled in a wireless fashion may, alternatively, be coupled in a wired fashion, and apparatus for communication and power transmission which are shown to be coupled in a wired fashion may, alternatively, be coupled in a wireless fashion. 

1.-289. (canceled)
 290. A method for treating a subject, comprising: applying electrical stimulation to a site of the subject selected from the group consisting of: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, and a lesser deep petrosal nerve; and configuring the stimulation to excite nervous tissue of the site at a strength that (a) is sufficient to induce at least one neuroprotective occurrence selected from the group consisting of: an increase in cerebral blood flow (CBF) of the subject, and a release of one or more neuroprotective substances, and (b) is insufficient to induce a significant increase in permeability of a blood-brain barrier (BBB) of the subject.
 291. The method according to claim 290, wherein configuring the stimulation comprises setting the strength to less than 90% of a strength sufficient to induce the significant increase in the permeability of the BBB.
 292. The method according to claim 290, wherein configuring the stimulation comprises setting the strength to less than 40% of a strength sufficient to induce the significant increase in the permeability of the BBB.
 293. The method according to claim 290, wherein configuring the stimulation comprises setting the strength to more than 50% of a strength sufficient to induce the significant increase in the permeability of the BBB.
 294. The method according to claim 290, wherein the site includes the SPG, and wherein applying the stimulation comprises applying the stimulation to the SPG.
 295. The method according to claim 294, wherein applying the stimulation comprises: placing an elongated support element within a greater palatine canal of the subject, sized to extend from a palate of the subject to the SPG, and having a distal end; and applying the stimulation from a vicinity of the distal end of the support element. 296.-306. (canceled)
 307. The method according to claim 290, wherein configuring the stimulation comprises configuring the stimulation to induce the at least one neuroprotective occurrence without producing a measurably-harmful clinical effect for the subject. 